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1
Bayard, Max, and Jim Holt. "Non-Alcoholic Fatty Liver Disease." Digital Commons @ East Tennessee State University, 2007. https://dc.etsu.edu/etsu-works/6495.
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Levene, Adam Phillip. "Steatosis in non alcoholic fatty liver disease." Thesis, Imperial College London, 2012. http://hdl.handle.net/10044/1/9691.
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Non-alcoholic fatty liver disease is the commonest cause of chronic liver disease in developed countries. The accurate assessment of steatosis is central to the diagnosis of non-alcoholic fatty liver disease. I compared the assessment of steatosis by histology, biochemical triglyceride assays, digital image analysis, with and without Oil Red-O staining, in mouse livers and human liver biopsies. In each case Oil Red-O digital image analysis was the most reliable technique for quantitating steatosis. I then investigated a potential, non-invasive technique for distinguishing steatosis from steatohepatitis as only the latter causes progressive liver disease. The liver contains fluorophores which can be detected by autofluorescence spectroscopy. The fluorophore levels vary depending on the levels of oxidative stress and fibrosis within the liver. Mouse and human livers, were assessed to measure the fluorescence intensity at different wavelengths and this was compared with the histology. The probe was able to accurately identify biopsies which had inflammation and fibrosis with a high degree of sensitivity and specificity. Autophagocytosis has recently been suggested to play a role in fat metabolism. Using liver differentiated HUH7 cells grown in normal or oleate containing media with or without Rapamycin (an autophagocytosis activator) the role of autophagocytosis was investigated. This involved examining steatosis by Oil Red-O digital image analysis, biochemical triglyceride assays, electron microscopy and confocal immunofluorescence. I concluded that activating autophagocytosis decreased the levels of steatosis within the cells. This work has shown Oil Red-O digital image analysis is the most accurate way of assessing steatosis within the liver, that autofluorescence spectroscopy has the ability to distinguish, in real-time, isolated steatosis from steatohepatitis and that autophagocytosis has a role in fat metabolism within the liver which may be exploited therapeutically.
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De, Alwis Nimantha M. W. "Mitochondrial dysfunction in non alcoholic fatty liver disease." Thesis, University of Newcastle Upon Tyne, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.493235.
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Non Alcoholic fatty Liver disease (NAFLD) is the commonest chronic liver disease worldwide and is a spectrum which includes simple fatty liver (simple steatosis), non-alcoholic steatohepatitis (NASH) and cirrhosis. Simple steatosis is a benign condition but NASH may progress to liver fibrosis and cirrhosis. Why only some develop progressive disease is not known and maybe dependant on the pathophysiology.
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Liu, Yang-Lin. "Genomic studies in non-alcoholic fatty liver disease." Thesis, University of Newcastle upon Tyne, 2017. http://hdl.handle.net/10443/3822.
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Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum that spans simple steatosis, through steatohepatitis (NASH) to fibrosis and ultimately cirrhosis. NAFLD is characterised by substantial inter-patient variation in rate of progression and disease outcome: whilst up to 25% of the general population are at risk of progressive disease, only a minority experience associated liver-related morbidity. Inter-patient genetic variation and environment determine severity and progression of NAFLD. This thesis reports a series of studies examining the association of genetic variations in two genes patatin-like phospholipase domain-containing 3 (PNPLA3, rs738409 c.444 C > G, p.I148M) and transmembrane 6 superfamily member 2, (TM6SF2, rs58542926 c.449 C > T, p.E167K) with severity of NAFLD and risk of NAFLD-associated hepatocellular carcinoma (HCC). Addressing first the role of PNPLA3, I demonstrate that the rs738409 variant is associated with steatosis, steatohepatitis and fibrosis in the largest histologically characterised NAFLD cohort of European-Caucasian descent (n=1,005) studied to date. Subsequently, adopting a case-control analyses in a cohort of 100 consecutive Northern European Caucasian patients with NAFLD-associated HCC arising and a cohort of patients with histologically characterised NAFLD, I demonstrate that carriage of the rs738409 minor (G) allele is significantly associated with increased risk of developing NAFLD-associated HCC, independent of potential confounding factors including gender, age at diagnosis, presence of advanced fibrosis/cirrhosis, T2DM and BMI. During my studies, a genome-wide association study identified a SNP in TM6SF2 as a modifier of hepatic triglyceride accumulation measured by MR Spectroscopy. It was therefore pertinent to determine whether this variant also affected risk of steatohepatitis or fibrosis in NAFLD. Using the aforementioned cohorts, I demonstrate for the first time that, in addition to its association with steatosis, the rs58542926 SNP is significantly associated with stage of fibrosis in NAFLD. In contrast to PNPLA3 however, no association with NAFLD-HCC was found. In conclusion, the current thesis confirms the association of PNPLA3 with NAFLD severity and provides new evidence of its association with HCC risk. In addition, itdemonstrates for the first time that TM6SF2 is associated with NAFLD-fibrosis severity. These studies provide important new insights into NAFLD pathogenesis and mandate further functional study.
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Scorletti, Eleonora. "Effect of omega-3 fatty acids in non-alcoholic fatty liver disease." Thesis, University of Southampton, 2017. https://eprints.soton.ac.uk/422265/.
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The first chapter (Introduction) of the thesis summarises the pathogenesis of NAFLD and its associated risk factors such as type 2 diabetes and cardiovascular disease. Moreover, it describes: a) the potential beneficial effects of long chain omega-3 fatty acid treatment [docosahexaenoic acid (DHA) plus eicosapentaenoic acid (EPA)] in NAFLD; b) the effect of genotypes patatin-like phospholipase domain-containing protein-3 (PNPLA3 I148M) and the transmembrane 6 superfamily member 2 protein (TM6SF2 E167K), on the level of DHA and EPA enrichment and end of study liver fat percentage after DHA+EPA treatment; and c) the effect of fatty acid desaturase (FADS) and Elongase (ELOVL) polymorphisms influencing omega-3 fatty acid metabolism. The second chapter describes the overall aim of this thesis. The aim of my research was to investigate in patients with NAFLD: a) the effect of long-chain omega-3 fatty acid treatment on liver fat percentage and liver fibrosis biomarkers; b) the effect of genotypes influencing NAFLD severity on treatment with DHA+EPA; and c) the effect of genotypes influencing omega-3 fatty acid metabolism in NAFLD. The third chapter describes in details the design and methods used in my research. Chapter four highlights my novel results from the WELCOME study. This chapter describes the baseline and end of study characteristics of the WELCOME study participants and shows the results of the DHA+EPA treatment on liver fat percentage and liver fibrosis biomarkers. This chapter also describes the association between DHA erythrocyte enrichment and decrease in liver fat percentage after DHA+EPA treatment. Chapter five illustrates the association between PNPLA3 I148M and DHA erythrocyte enrichment percentage and end of study liver fat percentage after DHA+EPA treatment. The chapter shows that PNPLA3 I148M was associated with higher end of study liver fat percentage and lower DHA tissue enrichment. Chapter six shows the negative association between FADS polymorphisms and omega-3 fatty acid metabolism in NAFLD. The chapter also shows that there was a gene-DHA+EPA interaction between the minor allele of the FADS1 rs174556 and Δ-5 desaturase activity after treatment with DHA+EPA. Finally, chapter seven, summarises my results in the context of current evidence and knowledge about the subject matter.
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Spanos, Christos. "Quantitative liver proteomics for biomarker discovery in non-alcoholic fatty liver disease." Thesis, University of Surrey, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.616323.
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Non-alcoholic fatty liver disease (NAFLD) is now the most common liver disease worldwide. Given that NAFLD can progress from steatosis to non-alcoholic steatohepatitis (NASH), fibrosis and potentially hepatocellular carcinoma, early diagnosis and accurate disease staging are primary clinical concerns. Hypothesizing that a subset of liver proteins will exhibit differential expression in NAFLD and that these proteins may represent candidate disease biomarkers; the aims of this project were to use proteomics to identify differentially expressed proteins both in an in vitro and an in vivo model of NASH. Preliminary studies developed and characterised both models used here; experiments utilized a relative quantitative proteomic approach with isobaric tags for relative and absolute quantitation labelling combined with nano-liquid chromatography and tandem mass spectrometry.
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Hallsworth, Kate. "Physical activity, exercise and non-alcoholic fatty liver disease." Thesis, University of Newcastle upon Tyne, 2012. http://hdl.handle.net/10443/1510.
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Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of liver conditions ranging from hepatic steatosis through steatohepatitis to cirrhosis. Its prevalence has been estimated at between one-in-five and one-in-three of the adult population depending on country and diagnostic criteria used. Prevalence increases with degree of obesity, and is very common in those with Type 2 diabetes (T2DM). Rising prevalence of obesity and T2DM, particularly in younger people, will ensure that NAFLD remains a growing clinical concern for the future. Lifestyle modification, which encompasses diet, weight loss, physical activity, and/or exercise related behaviours, is the primary recommended therapy for NAFLD, especially in the absence of approved pharmaceutical agents. Despite lifestyle modifications being central to the management of NAFLD, the evidence base upon which these guidelines are based is lacking, and this is particularly true for physical activity and exercise. The focus of this thesis is on defining, exploring and developing the evidence for physical activity and exercise in NAFLD with a view to improving clinical care. The work contained within this thesis demonstrates that low levels of physical activity are prominent in people with NAFLD and that targeting this with resistance exercise therapy confers benefits to both liver lipid and the factors promoting its accumulation. It also highlights alterations in cardiac structure and function in people with NAFLD in the absence of overt cardiac disease, which may provide a therapeutic avenue in which to decrease cardiac disease risk in people with fatty liver. Over the duration of the work described in this thesis, the number of studies reporting on exercise and liver fat in people with NAFLD has increased markedly. The new information contained within this thesis contributes to this body of knowledge and, over time, will improve the management of a condition that is an increasing burden to the people of the Western world.
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Cheng, Lik-fai, and 鄭力暉. "Non-alcoholic fatty liver disease in Asia: a systematic review." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2010. http://hub.hku.hk/bib/B45171117.
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Ekstedt, Mattias. "Non-Alcoholic Fatty Liver Disease : A clinical and histopathological study." Doctoral thesis, Linköpings universitet, Gastroenterologi och hepatologi, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-17220.
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Fatty liver has previously often been associated with excessive alcohol consumption. During the last two decades, the interest in fatty liver occurring in non-drinkers i.e. non-alcoholic fatty liver disease (NAFLD) has increased dramatically. Today, NAFLD is considered as the most common liver disease in the developed world. It is strongly associated with obesity, insulin resistance, and hypertension. Thus, NAFLD is considered as the hepatic manifestation of the metabolic syndrome. The spectrum of NAFLD includes: simple fatty liver without necroinflammatory activity; non-alcoholic steatohepatitis (NASH), a condition characterised by hepatocellular injury, inflammation, and fibrosis; cirrhosis; and in some individuals hepatocellular carcinoma. The degree of steatosis in liver biopsies is usually assessed by a morphological semiquantitative approach in which the pathologist uses a four-graded scale: 0–3 or none, slight, moderate and severe. In this thesis we show that there is a considerable inter- and intraindividual variation in such scoring methods and that a more standardised and quantitative approach is preferable. The area/volume of fat in liver biopsies is greatly overestimated when assessed semiquantitatively. Moreover, the point counting technique has a better reproducibility than visual evaluation and should be preferred in estimates of liver steatosis. The long-term clinical and histopathological course of 129 consecutively enrolled NAFLD patients was studied. Mean follow-up (SD) was 13.7 (1.3) years. Survival of NASH patients was reduced compared with a matched reference population. These subjects more often died from cardiovascular and liver-related causes. Seven patients (5.4%) developed end-stage liver disease, including 3 patients with hepatocellular carcinoma. Most NAFLD patients will develop diabetes or impaired glucose tolerance in the long term. Progression of liver fibrosis is associated with more pronounced insulin resistance and significant weight gain. During follow-up, 17 patients had been prescribed a statin. At follow-up, patients on medication with statins had significantly higher BMI. Diabetes was significantly more common among patients on medication with statins and they had significantly more pronounced insulin resistance. However, they exhibited a significant reduction of liver steatosis at follow-up as opposed to patients not taking statins. Although patients under statin treatment exhibited a high risk profile for progression of liver fibrosis, only four patients on statin treatment progressed in fibrosis stage. It is concluded that statins can be prescribed safely in patients with elevated liver enzymes because of NAFLD. Alcohol consumption was evaluated with a validated questionnaire combined with an oral interview. In a multivariate analysis moderate alcohol consumption, particularly when frequency of heavy episodic drinking was analysed, consistent with the diagnosis of NAFLD to be set, was independently associated with fibrosis progression in NAFLD. The NAFLD activity score (NAS) is a newly proposed system to grade the necroinflammatory activity in liver biopsies of NAFLD patients. We evaluated the usefulness of the NAS in predicting clinical deterioration and fibrosis progression in our cohort of NAFLD patients. Although the NAS was independently associated with future risk of progressive fibrosis in NAFLD, the clinical usefulness of the score was limited due to significant overlap in clinical development between NAS-score groups.
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Alshaalan, Rasha. "Non-invasive diagnostic methods for non-alcoholic fatty liver disease." Thesis, McGill University, 2013. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=119567.
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Background: NAFLD is one of the most common causes of liver disease worldwide. It is a spectrum of disease characterized by macrovesicular steatosis of the liver that ranges from simple fatty liver (steatosis), to non-alcoholic steatohepatitis (NASH). NASH may eventually evolve to cirrhosis and end stage complication. Liver biopsy has long been considered the gold standard of reference to diagnose NAFLD but it is costly and invasive. Recently, non-invasive methods have been proposed. Aims and methods: The aim of this study was to investigate the accuracy of non-invasive methods including (Ultrasound, computed tomography scan, Xenon-133 scan, Hepatic steatosis index, Fibroscan, NAFLD fibrosis score, APRI index, and FIB-4 index) and their combination to diagnose steatosis and to diagnose significant liver fibrosis (>F2) and cirrhosis (F4) as compared to liver biopsy. We conducted a retrospective study of 114 NASH patients (79 males, mean age 49.6±10.6). All had adequate liver histology. Results: The distribution of fibrosis stage was as follows: F0-F1= 50%, F2=16.8%, F3=19.2%, F4=14%. The distribution of steatosis grade was as follows: grade 0-1=16%, grade2=53.3%, grade3=30.7%. The following tests correlated with fibrosis: APRI index (r=0.554), FIB-4(r=0.555), NAFLD fibrosis score (r=0.473), Fibroscan(r=0.586) and Hepatic Steatosis Index (HSI) (r=0.245). The FIB-4 and APRI index showed the best diagnostic accuracy for significant fibrosis as indicated by an Area Under the Curve (AUC) of 0.801 and 0.782, respectively. The FIB-4 showed the best AUC= 0.886 for cirrhosis. None of the following tests US, CT, HSI, and xenon-133 scan were considered correlated significantly. The best combination algorithm for the detection of cirrhosis was gender and FIB-4 with an AUC of 0.8937. Conclusion: this study demonstrates that non-invasive methods for liver fibrosis are accurate to diagnose >F2 and F4. Severe steatosis cannot be reliably diagnosed by non-invasive methods. Notably, a combination of FIB-4 and gender significantly improves the performance of the single method for cirrhosis. These methods may help reducing the number of liver biopsies stratifying NASH patients that should start a screening program for HCC and esophageal varices.Contexte : La stéatose hépatique non alcoolique (SHNA) est l'une des causes les plus répandues des maladies du foie à l'échelle mondiale. Il s'agit d'un spectre de maladies qui se caractérise par une stéatose hépatique macrovésiculaire allant de la stéatose hépatique simple (stéatose) à la stéatohépatite non alcoolique (NASH). La NASH peut éventuellement évoluer vers une cirrhose et des complications en phase terminale. La biopsie du foie a longtemps été considérée comme la norme de référence par excellence pour le diagnostic de la SHNA, mais elle est coûteuse et invasive. Des méthodes non invasives ont récemment été proposées. Objectifs et méthodes : La présente étude avait pour objectif d'évaluer la précision de certaines méthodes non invasives (notamment les ultrasons [US], la tomographie par ordinateur [TO], la scintigraphie au xénon 133, l'indice de stéatose hépatique (ISH), la technique Fibroscan, le score de fibrose de SHNA, l'indice de ratio entre l'aspartate aminotransférase et les plaquettes [APRI] et l'indice FIB-4) et de l'utilisation combinée de ces méthodes pour le diagnostic de la stéatose et pour le diagnostic d'une fibrose hépatique significative (> F2) et de la cirrhose (F4), par comparaison à la biopsie du foie. Nous avons réalisé une étude rétrospective sur 114 patients atteints de NASH (79 patients de sexe masculin, âge moyen de 49,6 ans ± 10,6). Tous ces patients présentaient une histologie hépatique adéquate.Résultats : La répartition des stades de fibrose était la suivante : F0 F1 = 50 %, F2 = 16,8%, F3 = 19,2 %, F4 = 14 %. La répartition des stades de stéatose était la suivante : stade 0-1 = 16 %, stade 2 = 53,3 %, stade 3 = 30,7 %. Les tests suivants ont été mis en corrélation avec la fibrose : l'indice APRI (r = 0,554), l'indice FIB-4 (r = 0,555), le score de fibrose de SHNA (r = 0,473), la technique Fibroscan (r = 0,586) et l'indice de stéatose hépatique (r = 0,245). L'indice FIB-4 et l'indice APRI ont offert la meilleure précision diagnostique en ce qui concerne la fibrose significative, comme l'indiquent la surface sous la courbe (SSC) de 0,801 et la SSC de 0,782 respectivement. L'indice FIB-4 a présenté la meilleure SSC, soit 0,886, pour ce qui est de la cirrhose. Aucun des tests suivants, c'est à dire les tests aux US, la TO, l'ISH, et la scintigraphie au xénon 133, n'était considéré comme étant corrélé significativement. Le meilleur algorithme de combinaison pour le dépistage de la cirrhose était le sexe et l'indice FIB-4 avec une surface sous la courbe de 0,8937. Conclusion: cette étude démontre que les méthodes non invasives de diagnostic de la fibrose hépatique sont précises en ce qui concerne les stades > F2 et F4. La Stéatose sévère ne peut être diagnostiqué de façon fiable par des méthodes non invasives Notamment, une combinaison de l'indice FIB-4 et du sexe améliore considérablement le rendement de la méthode unique en ce qui a trait à la cirrhose. Ces méthodes pourraient aider à réduire le nombre de biopsies du foie visant à stratifier les patients atteints de NASH qui devraient entreprendre un programme de dépistage du carcinome hépatocellulaire (CHC) et des varices œsophagiennes.
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Qin, Minhua. "Regulation of genes in patients with non-alcoholic fatty liver disease /." [St. Lucia, Qld.], 2004. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe18501.pdf.
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Krasnoff, Joanne B. "Health-related fitness, physical activity, and non-alcoholic fatty liver disease." [Bloomington, Ind.] : Indiana University, 2007. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3274261.
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Thesis (Ph.D.)--Indiana University, School of Health, Physical Education and Recreation, 2007.Source: Dissertation Abstracts International, Volume: 68-07, Section: B, page: 4315. Adviser: Janet P. Wallace. Title from dissertation home page (viewed Apr. 15, 2008).
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Krishnan, Smitha. "Gut Microbiota Metabolites Modulate Inflammation in Non- Alcoholic Fatty Liver Disease." Thesis, Tufts University, 2018. http://pqdtopen.proquest.com/#viewpdf?dispub=10812893.
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Recent findings, including our own work, demonstrated that intestinal microbiota species produce bioactive metabolites that engage host cellular pathways. Microbiota-derived metabolites have also been detected in circulation and in the, setting up the intriguing possibility that these bacterial products could directly interact with host cellular pathways at distant sites. The study described in this abstract investigates the hypothesis that gut microbiota dysbiosis perturbs the balance of immunomodulatory microbiota metabolites, which exacerbates liver inflammation in steatosis. We utilize a multi-omic approach to identify microbiota-dependent immunomodulatory metabolites and characterize their effects on liver inflammation and metabolic function. In summary, we show that the levels of AAA-derived microbiota metabolites are significantly depleted in a diet model of liver steatosis, and that these metabolite can act directly on hepatocytes to modulate inflammatory pathways. Our results also show that the microbiota metabolites are ligands for the AhR, which could provide a mechanistic link for the observed anti-inflammatory effects. Taken together, our findings support the hypothesis that dysbiosis of the gut microbiota could predispose the liver to inflammation in diet-induced steatosis through an altered microbiota metabolite profile. Prospectively, additional insights into the mechanisms underlying the link between microbiota dysbiosis and NAFLD could provide novel strategies to treat or prevent the progression of fatty liver diseases through the use of probiotics or postbiotics.
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Alghamdi, Shareefa. "Consequences of non-alcoholic fatty liver disease on drug-induced hepatocytoxicity." Thesis, University of Surrey, 2015. http://epubs.surrey.ac.uk/808210/.
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Non-alcoholic fatty liver disease (NAFLD) is characterised by the accumulation of lipid in liver. Liver is the principal organ involved in drug biotransformation. The central hypothesis of this project is that alterations in the liver environment due to lipid accumulation aggravate sensitivity of hepatocytes to toxicity of some commonly prescribed drugs (paracetamol, alcohol, phenobarbital, cisplatin or doxorubicin). The aim of this study was to investigate the effect of lipid overloading (steatosis) on drug cytotoxicity in the liver model Huh7 cell line. Hepatic steatosis was induced in Huh7 cells by exposing cells to 300 μM FFA mixture or 1 mM oleic acid. Impact of steatosis on drug toxicity was examined by co-treating the cells with FFA and paracetamol, alcohol, phenobarbital, cisplatin or doxorubicin. Cell viability MTT assay showed that neither 300 μM FFA mixture nor 1 mM OA caused significant reduction in cell viability after 24 h incubation. However, a significant reduction seen after incubation for 48 h, therefore for the subsequent experiments the time frame chosen was 24 h. The results showed that 300 μM FFA mixture did not induce a significant amount of intracellular lipid, whereas 1 mM OA induced significant amount of intracellular lipid. The subsequent experiments were carried out to test the hypothesis that lipid-loaded Huh7 cells are more sensitive to drug toxicity. Co-treatment with FFA and either paracetamol, ethanol or doxorubicin resulted in further reduction in cell viability. Phenobarbital resulted in enhanced cell viability, and no significant changes in cell viability observed after co-treatment with cisplatin. To investigate mode of cell death, caspase3/7 activity was measured as mediator of apoptosis. Generally, an advance apoptosis was observed in steatotic cells treated with the different drugs. Reactive oxygen species were measured as a possible trigger of apoptosis. A significant amount of ROS were generated by FFAs, and generally, drug treatment induced a higher significant amount of ROS in the steatotic Huh7 cells. To elucidate the specific changes observed upon treatment of steatotic cells with hepatotoxic drugs, a single FFA dose (300 μM FFA mixture) and a single drug (doxorubicin) were selected to identify major alterations in gene expression. The microarray data confirmed alterations in oxidative stress-related genes. Such changes were functionally relevant as confirmed by cellular assay and In-Cell Western blot. In conclusion, the hypothesised effect of steatosis on drug toxicity has been confirmed and steatosis may enhance drug toxicity through changing cellular oxidative state and activating the apoptotic pathway.
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Cepero, Donates Yuneivy. "Pathogenic role of IL-15 in non-alcoholic fatty liver disease." Mémoire, Université de Sherbrooke, 2014. http://hdl.handle.net/11143/5871.
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Abstract : Pro-inflammatory cytokines play a key role in pathogenesis of obesity and non-alcoholic fatty liver disease (NAFLD). IL-15 is a pro-inflammatory cytokine, which signals through a receptor complex composed of the IL-15 receptor (IL-15R) alpha chain, the IL-2/IL-15R beta chain and the common gamma chain. The functions of IL-15 have been extensively described in immune cells but less is known about its functions in others tissues such as the liver. The aim of this thesis is to investigate the role of IL-15 in fatty liver disease.
C57BL/6 wildtype (WT) and IL-15 knockout (Il15[superscript -/-]) mice were maintained on high fat diet (HFD) or normal control diet (NCD). After 16 weeks, body weight, liver mass, fat accumulation in the liver, serum lipid levels and gene expression in the liver were evaluated. Intrahepatic lymphocytes (IHL) were also analysed. Primary hepatocytes were stimulated with IL-15 and chemokines gene expression was studied. IHLs were examined in WT, Il15[superscript -/-] and Il15ra[superscript -/-], as well as in macrophage- and hepatocyte-specific Il15ra[superscript -/-] mice.
We found that IL-15 deficiency prevents weight gain and accumulation of lipids in the liver. Circulating levels of cholesterol and non-esterified fatty acids were elevated in WT mice but not in Il15[superscript -/-] mice. Hepatic expression of chemokines such as Ccl2, Ccl5 and Cxcl10 was increased in WT mice under HFD, but not in Il15[superscript -/-] mice. The livers of Il15[superscript -/-] and Il15ra[superscript -/-] mice also showed decreased expression of Tnfa and iNOS, and macrophage markers Cd68 and F4/80. Accordingly, stimulation of primary hepatocytes with IL-15 induced chemokine gene expression in WT but not in Il15ra[superscript -/-] hepatocytes. Furthermore, hepatocyte-specific ablation of IL-15Rαreduced infiltration of NK and NKT cells in the liver, suggesting that IL15Rα expression in the hepatocytes is needed for the recruitment and/or maintenance of the NK cell population in the liver.
In conclusion, IL-15 promotes fat accumulation in the liver, and this is associated with increased inflammatory response in the liver. Increased availability of IL-15 in obesity may stimulate hepatocytes to secrete chemokines that promote hepatic inflammation resulting in fatty liver disease. IL-15Rα expression in hepatocytes appears to play a role in the maintenance of NK, NKT and iNKT cells. // Résumé : Les cytokines pro-inflammatoires jouent un rôle important dans la pathogenèse de l’obésité et la stéatose hépatique. L'IL-15 est une cytokine pro-inflammatoire qui est trans-présentée par l'IL-15Rα aux chaines IL-2/IL-15Rβ et γc. La fonction de l'IL-15 a été largement décrite dans les cellules immunitaires, mais ses fonctions dans d'autres tissus sont moins connues. Le but de ce mémoire est d'élucider le rôle de l'IL-15 dans la stéatose hépatique.
Les souris C57BL/6 de type sauvage (WT) et Il15[indice supérieur -/-] ont été soumises à un régimehyperlipidique (HFD) ou à un régime normal. Après 16 semaines, le poids corporel, lamasse hépatique, l'accumulation de lipides dans le foie, les taux de lipides sériques et l'expression des différents gènes reliés à l’inflammation et au métabolisme dans le foie ont été évalués. Les lymphocytes intra-hépatiques (IHL) ont été également étudiés. Des hépatocytes primaires ont été stimulés avec IL-15, et l'expression génique de chimiokines a été déterminée. Les populations de IHLs ont été également caractérisées chez les souris WT, Il15[indice supérieur -/-] et Il15ra[indice supérieur -/-], ainsi que chez des souris dont la déficience dans l’expression d’IL-15Rα est ciblée aux macrophages ou aux hépatocytes.
Nos résultats montrent que la déficience en IL-15 empêche l'accumulation de lipides dans le foie. Les taux de cholestérol et d’acides gras non estérifiés dans le sang étaient élevés chez les souris WT, mais pas chez les souris Il15[indice supérieur -/-]. L'expression hépatique des chimiokines Ccl2, Ccl5, Cxcl10 et des marqueurs de macrophages était augmentée chez les souris WT sous HFD, mais pas chez les souris Il15[indice supérieur -/-]. La stimulation des hépatocytes primaires avec l'IL-15 induit l'expression des gènes des chimiokines chez les hépatocytes WT, mais pas chez les Il15ra[indice supérieur -/-]. En outre, nous avons trouvé une infiltration réduite des
cellules NK et NKT dans le foie des souris déficientes en Il15ra[indice supérieur -/-] dans les hépatocytes, ce qui suggère que l'expression d’IL15Rα chez les hépatocytes est nécessaire aurecrutement des cellules NK, NKT et / ou à leur maintien.
En conclusion, nous proposons que l’IL-15 favorise l'accumulation de lipides dans le foie,
et que ceci est associée à une réponse inflammatoire accrue. La disponibilité accrue de
l'IL-15 dans l'obésité pourrait stimuler les hépatocytes à secréter des chimiokines ce qui
favorise l'inflammation hépatique et conduirait à la stéatose hépatique. L’expression de
l'IL-15Rα dans les hépatocytes semble jouer un rôle principal dans l’infiltration des
cellules NK, NKT et iNKT dans le foie.
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Berlanga, Bustos Alba. "Deregulation of fatty acid metabolism and cannabinoid receptors in liver of morbidly obese women with non-alcoholic fatty liver disease." Doctoral thesis, Universitat Rovira i Virgili, 2015. http://hdl.handle.net/10803/325135.
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La malaltia del fetge gras no alcohòlic (MFGNA) inclou un espectre histològic que va des de la esteatosi simple (SS) a l'esteatohepatitis no alcohòlica (EHNA), sent aquesta última freqüentment progressiva. Donat que l'acumulació hepàtica de lípids sembla ser un mecanisme crucial en la patogènesi de la MFGNA, una millor comprensió dels mecanismes subjacents que condueixen a l'acumulació inicial de lipíds hepàtics podria ser de gran interès per controlar la progressió de la malaltia. El sistema endocannabinoide (SE), mitjançant principalment els receptors cannabinoides CB1 i CB2, sembla ser que juga un paper important en la patogènesi de la MFGNA modulant el metabolisme lipídic. Així, la hipòtesi establerta és que, en pacients amb MFGNA, l'expressió de gens i factors de transcripció implicats en la regulació del metabolisme lipídic hepàtic, així com l'expressió dels receptors cannabinoides pot estar alterada; i aquesta alteració podria estar relacionada amb l'aparició de dany hepàtic. En conseqüència, vam evaluar l'expressió hepàtica d'alguns gens clau involucrats en la síntesi de novo d'àcids grassos (AG), captació i transport d’AG, oxidació d’AG, inflamació, així com l’expressió de CB1 i CB2 en una extensa cohort de dones obeses mòrbides amb MFGNA segons la seva histologia hepàtica. La principal troballa ha estat que, en el fetge de dones obeses mòrbides amb SS, els gens clau involucrats en la síntesis de novo d’AG presenten una relació inversa amb el grau histològic d’esteatosi, suggerint que la via lipogènica podria estar disminuïda en etapes avançades d’SS. Respecte al SE, els nostres resultats suggereixen un paper perjudicial de CB1 en la MFGNA, mentre que el rol de CB2 no és del tot aclarit.La enfermedad del hígado graso no alcohólico (EHGNA) incluye un espectro histológico que va desde la esteatosis simple (SS) a la esteatohepatitis no alcohólica (EHNA), siendo esta última frecuentemente progresiva. Dado que la acumulación hepática de lípidos parece ser un mecanismo crucial en la patogénesis de la EHGNA, una mejor comprensión de los mecanismos subyacentes que conducen a la acumulación inicial de lípidos hepáticos podría ser de gran interés para controlar la progresión de la enfermedad. El sistema endocannabinoide (SE), mediado principalmente por los receptores cannabinoides CB1 y CB2, parece juegar un papel importante en la patogénesis de la EHGNA modulando el metabolismo lipídico. Así, la hipótesis establecida es que, en pacientes con EHGNA, la expresión de genes y factores de transcripción implicados en la regulación del metabolismo lipídico hepático, así como la expresión de los receptores cannabinoides puede estar alterada; y esta alteración podría estar relacionada con la aparición de daño hepático. En consecuencia, evaluamos la expresión hepática de algunos genes clave involucrados en la síntesis de novo de ácidos grasos (AG), captación, transporte y oxidación de AG, inflamación, así como la expresión de CB1 y CB2 en una extensa cohorte de mujeres obesas mórbidas con EHGNA según su histología hepática. El principal hallazgo fue que, en el hígado de mujeres obesas mórbidas con SS, los genes clave involucrados en la síntesis de novo de AG presentan una relación inversa con el grado histológico de esteatosis, sugiriendo que la via lipogénica podría estar disminuida en estadios avanzados de esteatosis. Respecto al SE, nuestros resultados sugieren un papel perjudicial de CB1 en la EHGNA, mientras que el papel de CB2 no es del todo esclarecido.
Non-alcoholic fatty liver disease (NAFLD) encompasses a histological spectrum from simple steatosis (SS) to non-alcoholic steatohepatitis (NASH), with the latter being more frequently progressive. Due to lipid accumulation in the human liver seems to be a crucial mechanism in the NAFLD pathogenesis, an improved understanding of the underlying mechanisms leading to the initial hepatic lipid accumulation could be of great interest for controlling the progression of NAFLD. It has also been reported that the endocannabinoid (EC) system, mediated mainly by CB1 and CB2 cannabinoid receptors, plays an important role in NAFLD pathogenesis by modulating lipid metabolism. We therefore hypothesized that in patients with NAFLD, the expression of genes and transcription factors involved in the regulation of hepatic lipid metabolism, as well as the expression of cannabinoid receptors could be altered; and this alteration may be related to the onset of liver damage. Consequently, we wished to further investigate the fatty acid (FA) metabolism and the EC system by evaluating the hepatic expression of some key genes involved in de novo synthesis FA, FA uptake and transport, FA oxidation, and inflammation; as well as CB1 and CB2 expression in an extensive cohort of morbidly obese (MO) women according to their liver histology. The major finding is that, in liver of MO women with SS, the key genes related to de novo fatty acid synthesis have an inverse relationship with the histological degree of simple steatosis; suggesting that the lipogenic pathway seems to be down-regulated in advanced stages of SS. Regarding the EC system, our results suggest a deleterious role of CB1 in NAFLD, while the role of CB2 is not fully clarified.
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Pang, Zhenyi. "Non-alcoholic fatty liver disease : real-time PCR analysis of gene expression /." [St. Lucia, Qld.], 2004. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe.pdf.
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Pugh, Christopher James Alan. "Vascular and metabolic adaption to exercise in non-alcoholic fatty liver disease." Thesis, Liverpool John Moores University, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.570720.
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Non-alcoholic fatty liver disease (NAFLD) is characterised by the accumulation of fat in the liver and is associated with liver-related morbidity and mortality. Nevertheless, the leading cause of death in these patients is cardiovascular disease (CVD). Excess abdominal visceral adipose tissue (VAT) is frequently expressed in NAFLD and is considered a pivotal feature in the pathogenesis ofNAFLD which is predictive of CVD. Endothelial dysfunction is an early manifestation in the development of atherosclerosis and is characterised bya diminished bioavailabilty of the anti-atherogenic molecule NO, which is secreted by the endothelium of all blood vessels throughout the vascular tree. Limited pharmacological treatment is available to reduce hepatic fat, therefore, lifestyle modification interventions comprised of structured exercise and diet are recommended as a non-pharmacological management strategy to reduce hepatic fat in NAFLD. The primary aim of this thesis was to explore nitric oxide (NO)-mediated endothelial function at different levels of the vascular tree in NAFLD patients and to establish whether supervised exercise training has a sustained therapeutic impact on endothelial function. Thirty-two NAFLD patients (21 males, 11 females, 48±2yrs, BMI 31±lkg/m2) and eighteen matched controls (8 males, 10 females, 48±2yrs, BMI 30±lkg/m2) underwent magnetic resonance imaging (MRI) to quantify abdominal VAT and proton magnetic resonance spectroscopy (lH-MRS) to determine intrahepatocellular triglyceride content (IHTC). Brachial artery flow mediated dilatation (FMD) (as an index of endothelial NO function) was also assessed. IHTC (27.2±3.0 vs. 2.9±0.4%) and abdominal VAT (S.4±0.3vs. 3.4±0.2 1) were elevated in NAFLD patients when compared with controls (P
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Boateng, Anthony Osei. "Hepatoprotective properties of Gentiana spp. against non-alcoholic fatty liver disease (NAFLD)." Thesis, University of Westminster, 2018. https://westminsterresearch.westminster.ac.uk/item/q4yzy/hepatoprotective-properties-of-gentiana-spp-against-non-alcoholic-fatty-liver-disease-nafld.
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Non-alcoholic fatty liver disease (NAFLD) is a metabolic disease characterised by the accumulation of fat in the liver. It is estimated that 33 % of the UK population have NAFLD with 2-5 % progressing to non-alcoholic steatohepatitis (NASH). Due to a lack of an outright therapy for NAFLD, treatment has been mainly focussed on managing the conditions associated with the disease such as obesity, diabetes mellitus and hyperlipidaemia. This study aimed to investigate the means by which hepatocyte protection is conferred by Gentiana plants (Gentiana lutea, Gentiana macrophylla, Gentiana scabra and Gentiana rigescens) used in herbal medicine for the management of non-alcoholic fatty liver diseases (NAFLD). The role played by some of the inherent Gentiana phytochemicals including: gentiopicroside, sweroside and swertiamarin in promoting hepatocyte protection against the cytotoxic effects of fatty acids were also investigated. Gentiana species: lutea, macrophylla, rigescens, and scabra are known to protect and enhance hepatocyte viability via their antioxidant, anti-inflammatory and bitter components including: amarogentin gentianine, iso-orientin, swertiamarin, gentiopicroside, and sweroside. This study was necessitated due to a lack of adequate research on the hepatoprotective effects of the above-named Gentiana species and phytochemicals with special emphasis on their effect on mitochondrial respiration in the presence of fatty acids. At the time of submission, this was the first study to utilise the seahorse mitochondria stress assay to investigate the Gentiana species as well as phytochemicals: gentiopicroside, sweroside and swertiamarin. It was also found that the most abundant phytochemical in all four Gentiana species was gentiopicroside (up to 4.6% g/g), followed by swertiamarin (0.21–0.45% g/g), and sweroside (0.03- 0.4 % g/g). Furthermore, it was also observed that the methanolic extracts of all four Gentiana protected HepG2 and THLE-2 cells by inhibiting arachidonic acid from diminishing cell replication but showed a mitogenic effect mostly observed in gentiopicroside, Gentiana lutea and Gentiana macrophylla. It was concluded that phytochemicals: gentiopicroside, sweroside and swertiamarin play key roles in the hepatocyte protection exerted by methanolic extracts of Gentiana lutea, Gentiana macrophylla, Gentiana scabra and Gentiana rigescens against the cytotoxic effects of fatty acids. This protection is conferred by enhancing mitochondrial function in terms of increasing maximal respiratory capacity in response to high influx of fatty acids, promoting ATP production as well as scavenging ROS produced as a result of high fatty acid influx and increased mitochondrial respiration. However, the mitogenic effect observed in gentiopicroside and Gentiana macrophylla requires further studies using unmodified primary hepatocytes to gain better understanding.
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Wong, Yue-ling, and 黃愉鈴. "The role of adipocyte fatty acid binding protein in the pathogenesis of non-alcoholic fatty liver disease." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2010. http://hub.hku.hk/bib/B45164873.
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Satishchandran, Abhishek. "The Mechanistic Role and Therapeutic Potential of microRNA-122 in Alcoholic Liver Disease: A Dissertation." eScholarship@UMMS, 2016. https://escholarship.umassmed.edu/gsbs_diss/838.
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Chronic alcohol use results in accelerated liver injury, leading to alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma. However, due to the complex nature of this disease process, a central, druggable mechanism has remained elusive. microRNAs are potent post-transcriptional regulators of gene expression. A single miRNA has the ability to regulate hundreds of pathways simultaneously, defining cellular fate and function. microRNA-122 (miR-122), the most abundant miRNA in hepatocytes, has a demonstrated role as an tumor suppressor, regulator of hepatocyte metabolism, and hepatic differentiation.
In this dissertation I demonstrate the role of miR-122 on alcoholic liver disease (ALD) pathogenesis over four parts. In chapter II, I will demonstrate chronic alcoholic patients, free of neoplastic changes, have a reduction of miR-122 and that this miRNA regulates HIF-1α, a determinant of ALD pathogenesis. In chapter III, using hepatocytetropic adeno-associated virus 8 (AAV8) vector, I demonstrate that miR-122 inhibition mimics ALD pathogenesis, and furthermore, using hepatocyte-specific HIF-1α-null (HIF1hepKO) mice that this phenomenon is HIF-1α dependent. Given this finding, in chapter IV, I demonstrate that ectopic expression of miR-122 in vivo can reverse alcoholinduced liver damage, steatosis, and inflammation by directly targeting HIF-1α. Finally, in chapter V, I present evidence that alcohol-induced dysregulation of grainyhead-like proteins 1 and 2 (GRHL2), mediate the inhibition of miR-122 at the transcriptional level. These findings dissect a novel mechanistic regulatory axis of miR-122 and indicate a potential opportunity for restoration of miR-122 as a therapy in early ALD.
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Satishchandran, Abhishek. "The Mechanistic Role and Therapeutic Potential of microRNA-122 in Alcoholic Liver Disease: A Dissertation." eScholarship@UMMS, 2004. http://escholarship.umassmed.edu/gsbs_diss/838.
Full textAbstract:
Chronic alcohol use results in accelerated liver injury, leading to alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma. However, due to the complex nature of this disease process, a central, druggable mechanism has remained elusive. microRNAs are potent post-transcriptional regulators of gene expression. A single miRNA has the ability to regulate hundreds of pathways simultaneously, defining cellular fate and function. microRNA-122 (miR-122), the most abundant miRNA in hepatocytes, has a demonstrated role as an tumor suppressor, regulator of hepatocyte metabolism, and hepatic differentiation.
In this dissertation I demonstrate the role of miR-122 on alcoholic liver disease (ALD) pathogenesis over four parts. In chapter II, I will demonstrate chronic alcoholic patients, free of neoplastic changes, have a reduction of miR-122 and that this miRNA regulates HIF-1α, a determinant of ALD pathogenesis. In chapter III, using hepatocytetropic adeno-associated virus 8 (AAV8) vector, I demonstrate that miR-122 inhibition mimics ALD pathogenesis, and furthermore, using hepatocyte-specific HIF-1α-null (HIF1hepKO) mice that this phenomenon is HIF-1α dependent. Given this finding, in chapter IV, I demonstrate that ectopic expression of miR-122 in vivo can reverse alcoholinduced liver damage, steatosis, and inflammation by directly targeting HIF-1α. Finally, in chapter V, I present evidence that alcohol-induced dysregulation of grainyhead-like proteins 1 and 2 (GRHL2), mediate the inhibition of miR-122 at the transcriptional level. These findings dissect a novel mechanistic regulatory axis of miR-122 and indicate a potential opportunity for restoration of miR-122 as a therapy in early ALD.
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Purwaha, Preeti. "Effect of Dietary Omega-3 and Omega-6 Polyunsaturated Fatty Acids on Alcoholic Liver Disease." Diss., North Dakota State University, 2012. https://hdl.handle.net/10365/26488.
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PUFAs have been shown to modulate ALD by several mechanisms, including free radical generation from hepatic lipid peroxidation. However, how they modulate lipid peroxidation and generation of bioactive metabolites in ALD is poorly understood and it is still not clear which PUFAs (?-3 or ?-6) are beneficial or detrimental in ALD. Thus, our objective was to study the effect of ?-3/?-6 PUFAs on lipid peroxidation and ethanol mediated steatosis and inflammation. Using standard liquid diet (LDC), LDC with fish oil (rich in ?-3) and safflower oil (rich in ?-6), we studied the generation of bioactive metabolites, such as eicosanoids and free radicals generated via lipid peroxidation. In addition, we determined the effect of PUFAs on several inflammatory and fibrotic factors, e.g. gene as well as protein expression, using western blot and RT-PCR, respectively. We also investigated the effect of PUFA diets on novel targets, such as hepatic membrane transporters with potential role in liver inflammation. Our results suggest that ?-3 diet prevented while ?-6 based diets promoted the development of fatty liver and inflammation. ?-3 PUFA reduced AA-peroxidation by lowering hepatic AA concentration and expression of peroxidation enzymes, COX-2 and 5-LOX, resulting in lower generation of pro-inflammatory AA-derived PGs (Series-2), HETEs and free radicals, along with increase in anti-inflammatory EPA and DHA-derived PGs (Series-3). ?-3 diet might also reduce liver inflammation by preventing activation of NF-?B and induction of TNF-?. Rats fed with ?-3 diet showed high protein expression of efflux transporters, MRP-2 and ABCA1, indicating elimination of peroxidation metabolites and triglycerides from the liver and decreased inflammation. In contrast, ?-6 diets led to increase in AA-peroxidation and generation of AA-derived pro-inflammatory metabolites. ?-6 based diets also promoted fatty liver and inflammation by activating NF-?B, inducing TNF-? and downregulation of efflux transporters, MRP-2 and ABCA1. This study not only provides new insights into the effects and possible mechanisms by which ?-3 and ?-6 PUFAs may alter hepatic steatosis and inflammation, but also put forward new targets of research, such as hepatic membrane transporters in relation to liver pathology in ALD.
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Fisher, Craig. "Non-Alcoholic Fatty Liver Disease Alters the Three Stages of Hepatic Drug Management." Diss., The University of Arizona, 2008. http://hdl.handle.net/10150/195795.
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In pharmacotherapeutics, the term "correct dosing" is based on the concept that too high a systemic concentration will lead to drug toxicity, while drug levels that are too low may not produce the intended therapeutic effect. Often, the factors determining the ability of a patient to manage a given dose rely on their capacity to efficiently metabolize and eliminate drugs from the body. The liver plays a crucial role in the processing of many clinically relevant drugs via three stages of hepatic drug management. Drugs must first be taken into hepatocytes by uptake transporters. Drugs are then metabolized by phase I and phase II enzymes to make them more manageable. Finally, metabolites are removed from the hepatocyte by efflux transporters either into the bile for elimination or reintroduction to systemic blood. Alterations in one or more of the hepatic drug management stages increase the potential for adverse drug reactions (ADRs).In the United States, ADRs account for between 3%-12% of admissions to hospitals, and approximately 5% of deaths each year. While less than 20% of these cases are due to genetic polymorphisms, the vast majority of ADRs are due to environmental factors including disease. Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of conditions progressing from steatosis to non-alcoholic steatohepatitis (NASH) and often leading to cirrhosis. Presently, NASH patients represent the greatest population of candidates for liver transplant, illustrating the severity as well as the incidence of this disease. Patients with NAFLD are typically treated for co-existing conditions of the metabolic syndrome (i.e. hyperlipidemina or type II diabetes) and therefore represent a distinct population at risk for adverse drug reactions.The following studies show that experimental NAFLD affects both the signal transduction pathways regulating hepatic drug management genes as well as the hepatic uptake transporter function. Additionally, patient livers diagnosed with progressive stages of NAFLD, display altered CYP activity and efflux transporter expression similar to those previously reported in experimental NAFLD. Given that changes observed in experimental NAFLD result in functional changes in hepatic drug management, similar changes observed in patients with this disease suggest an increased risk for ADRs.
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Penke, Melanie. "The NAD salvage pathway during the progression of non-alcoholic fatty liver disease." Doctoral thesis, Universitätsbibliothek Leipzig, 2016. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-194821.
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Non-alcoholic fatty liver disease (NAFLD) is a major chronic liver disease and thus a main reason for liver-related morbidities and mortality. NAFLD covers a wide range of diseases starting with steatosis and frequently progressing to non-alcoholic steatohepatitis (NASH), which is an independent predictor for the development of the hepatocellular carcinoma (HCC). Nicotinamide phosphoribosyltransferase (NAMPT), the key enzyme of the mammalian NAD salvage pathway, recycles nicotinamide to nicotinamide mononucleotide (NMN), which is further converted to nicotinamide adenine dinucleotide (NAD). NAD is not only an important redox partner but also a crucial co-substrate for NAD-dependent enzymes such as sirtuin 1 (SIRT1). Thus, NAD metabolism might be involved in the progression of NAFLD by regulating many cellular processes, such as apoptosis, de novo lipogenesis, glycolysis and gluconeogenesis, in the liver. Interestingly, tumor cells have a high NAD turnover due to their rapid proliferation and high activity of NAD-dependent enzymes. For these reasons, I hypothesized that the NAD salvage pathway is dysregulated during the progression of non-alcoholic fatty liver disease.
Therefore, the first study of the present work deals with the role of the NAD salvage pathway in a diet-induced mouse model of hepatic steatosis. In mice fed a high-fat diet for 11 weeks hepatic NAMPT mRNA, protein abundance and activity as well as NAD levels were increased. Additionally, SIRT1 protein abundance was upregulated indicating a higher SIRT1 activity. This could be confirmed by detecting decreased acetylation or transcription of SIRT1 targets. For example, p53 and nuclear factor κB (NF-κB) were less acetylated demonstrating lower activity of key regulators of apoptosis and inflammation, respectively.
In the second study of this thesis NAMPT activity was inhibited by applying its specific inhibitor FK866 in hepatocarcinoma cells to investigate whether or not NAMPT inhibition could be a potential novel therapeutic approach in HCC treatment. Hepatocarcinoma cells were more sensitive to NAMPT inhibition by FK866 than primary human hepatocytes, presenting a high number of apoptotic cells after FK866 treatment. FK866 induced NAD and ATP depletion which was associated with activation of the key regulator of energy metabolism 5’-AMP-activated protein kinase (AMPK) and decreased activity of its downstream target mammalian target of rapamycin (mTOR).
This thesis shows that the NAD salvage pathway is involved in hepatic steatosis and HCC. During hepatic steatosis NAD metabolism is upregulated to potentially protect against adverse effects of the massive hepatic lipid accumulation. To repress the progression to NASH it might be useful to maintain the hepatic NAD levels during early disease stages by administration of NAD precursors, such as NMN. However, hepatocarcinoma cells have a higher activity of NAMPT and NAD-dependent enzymes. NAMPT inhibition by FK866 could be a potential therapeutic approach in HCC, especially due to the fact that NAD depletion is selectively induced in hepatocarcinoma cells, but not in primary human hepatocytes.
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Lyall, Marcus James. "TET mediated 5’hydroxymethylation in the pathogenesis of non alcoholic fatty liver disease." Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/29524.
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Non-alcoholic fatty liver disease (NAFLD) now affects around one in four adults in the human population and parallels the global increase in obesity. Within the spectrum of NAFLD, simple steatosis is associated with insulin resistance and type 2 diabetes while progression to steatohepatitis (NASH) is associated with an increased risk of liver cirrhosis and all-cause mortality. The molecular pathology of NAFLD is incompletely understood, however observational studies in human cohorts suggest the regulation of DNA methylation may play a role. 5-hydroxymethylcytosine (5hmC) is a cytosine modification generated from 5- methylcytosine (5mC) by the Ten eleven translocase isoenzymes (Tets) as part of a demethylation process. The aim of this project was to examine the role of Tet enzyme activity on the pathogenesis and progression of NAFLD. Detailed characterisation of two established murine dietary interventions allowed the selection of a NAFLD mouse model which broadly recapitulated the metabolic, histological and transcriptional features of human disease. Using DNA immunoprecipitation coupled with whole genome next generation sequencing and RNA micro expression arrays I examined the effect of high fat diet feeding (HFD) on hepatic DNA 5hmC levels within annotated gene regions. Whilst the global 5hmC profile was not altered by HFD, there was profound genic enrichment of 5hmC in upregulated mediators of cholesterol synthesis and transport (Lss, Sc4mol, Fdps, Hsd17b7, Cyp17a1, Mvd, Cyp1a2, Dhcr7 and Apoa4) with no enrichment in genes with other pathological functions (drug detoxification, inflammation, cell cycle regulation). Induced peaks of 5hmC enrichment were subsequently abolished following rescue of the NAFLD phenotype by conversion to control diet. Cross species validation was performed in vitro utilising embryonic stem cell derived hepatocytes challenged with a cocktail of high energy substrates. My in vivo findings were broadly replicated with specific 5hmC enrichment in genes synthesising lipotoxic molecules (PLIN2, CIDEC, APOA4, ACADVL, HMGCS2, APOA5, CYP2J2, IGFBP1, PPAP2C, ACSL1, APOC3, ANGPTL4, NRG1) with no enrichment in upregulated genes of alternative function. To determine whether or not the 5hmC enrichment seen is of functional relevance, I studied Tet1-/- C57BL/6J mice. Tet1-/- mice are grossly normal in appearance, however loss of Tet1 conferred a striking resistance to diet induced obesity with reduced body fat mass, improved insulin-sensitivity and near complete absence of NAFLD compared to wild type littermates. Furthermore, the HFD fed Tet1-/- liver transcriptome showed a ‘protective’ profile, with suppression of genes for lipid synthesis, inflammation and fibrosis. Thus, in multiple cross-species models of NAFLD, over nutrition induces genic hydroxymethylation specifically within activated genes driving the synthesis and transport of lipid molecules. Such changes are reversible with resolution of the NAFLD phenotype strengthening functional association. Tet1 deficiency conveys an obesity and NAFLD resistant phenotype. I therefore introduce Tet1 mediated hydroxymethylation as a novel mechanism for NAFLD pathogenesis.
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Käräjämäki, A. (Aki). "Non-alcoholic fatty liver disease (NAFLD):perspectives to etiology, complications and lipid metabolism." Doctoral thesis, Oulun yliopisto, 2017. http://urn.fi/urn:isbn:9789526217376.
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Abstract Obesity, insulin resistance, type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) form a dangerous quartet which threatens human health all over the world. About 25% of adults around the world have NAFLD, which poses risks for cardiovascular and metabolic well-being and may develop into liver cirrhosis and hepatocellular carcinoma. Apart from lifestyle modification, treatment options for NAFLD are scarce. This thesis presents atrial fibrillation (AF) as a new complication of NAFLD among general population of 958 individuals aged 40-60 years participating in the OPERA study. Even after multiple-adjustments for confounding factors, ultrasound-based NAFLD predicted the development of AF during about 16 years of follow-up. Moreover, the association between AF and liver fibrosis in 76 individuals aged 64-82 years in a cross-sectional setting is presented. The thesis also shows that individuals with metabolic syndrome (MetS), with or without NAFLD, are at increased risk of cardiovascular events, T2D and the increase of left ventricular mass index in a study population of 958 individuals aged 40-60 years during a 20-year follow-up. In other words, NAFLD without MetS does not seem to expose to these three cardiometabolic complications. The thesis also shows that rifampicin-activated pregnane X receptor (PXR), a member of the nuclear receptor superfamily of ligand-activated transcription factors with several endobiotic and xenobiotic activators, increases serum levels of cholesterol, phospholipids and certain fatty acids, assessed by nuclear magnetic resonance metabolomics technique, in a randomized, open, placebo-controlled trial among 34 young and healthy individuals. These serum lipids are considered toxic lipids and capable of transforming hepatosteatosis into steatohepatitis and even more severe forms of NAFLD. Moreover, rifampicin-activated PXR has no effect on serum triglycerides, that are non-toxic lipids, or triglyceride accumulation in the liver, assessed by magnetic resonance imaging, in 15 young and healthy individuals. In conclusion, this thesis advances the knowledge in the pathogenesis, lipid metabolism, complications and heterogeneous nature of NAFLD. These may have implications for patient care and follow-upTiivistelmä Maailmanlaajuisesti noin 25% täysi-ikäisistä henkilöistä sairastaa alkoholinkäyttöön liittymätöntä rasvamaksaa. Sen tiedetään altistavan sydän- ja verisuonisairauksille, aineenvaihduntahäiriöille, maksakirroosille ja jopa maksasyövälle, mutta elämäntapahoitoa lukuun ottamatta hoitomahdollisuudet ovat toistaiseksi vähäisiä. Tässä väitöskirjassa osoitetaan ensimmäistä kertaa alkoholinkäyttöön liittymättömän rasvamaksan ennustavan itsenäisesti eteisvärinän ilmaantuvuutta noin 16 vuoden seurannan aikana 958 tavallisen keski-ikäisen ihmisen aineistossa osana OPERA-tutkimusta. Lisäksi väitöskirjassa osoitetaan maksan sidekudosmuodostuksen ja eteisvärinän välillä olevan yhteys poikkileikkausasetelmassa 76 iäkkään ihmisen muodostamassa aineistossa. Väitöstutkimuksessa havaittiin myös, että metabolista oireyhtymää sairastavilla henkilöillä on suurentunut tyypin 2 diabeteksen, sydän- ja verisuonisairauksien sekä vasemman kammion koon suurentumisen riski noin 20 vuoden seurannan aikana 958 tutkittavan henkilön aineistossa riippumatta siitä, onko heillä alkoholinkäyttöön liittymätön rasvamaksa. Toisin sanoen alkoholin käyttöön liittymätön rasvamaksa ilman metabolista oireyhtymää ei lisää edellä mainittujen kolmen sairauden riskiä. Väitöstutkimuksessa esitetään lisäksi, että rifampisiinilla aikaansaatu maksan pregnane X -reseptorin aktivaatio johtaa seerumin fosfolipidien, tiettyjen rasvahappojen sekä usean eri kolesterolityypin lisääntymiseen 34 terveen nuoren henkilön aineistossa. Kirjallisuudessa näiden seerumin rasva-aineiden on esitetty aiheuttavan alkoholin käyttöön liittymätöntä maksatulehdusta ja jopa rasvamaksan vakavimpia muotoja. Toisaalta rifampisiini ei lisännyt seerumin triglyseridipitoisuutta eikä aiheuttanut magneettitutkimuksella mitattuna triglyseridien kertymistä maksaan 15 terveen nuoren henkilön aineistossa. Tämä väitöstutkimus antaa lisätietoa rasvamaksan kehittymisestä, rasva-aineenvaihdunnasta ja komplikaatioista sekä korostaa rasvamaksan monimuotoista luonnetta. Nämä löydökset saattavat parantaa rasvamaksaa sairastavien henkilöiden hoitoa ja seurantaa
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Kruger, F. C. "A study of non-alcoholic fatty liver disease (NAFLD) in South African patients and analysis of candidate genes in insulin resistance and fatty acid oxidation." Thesis, Stellenbosch : Stellenbosch University, 2008. http://hdl.handle.net/10019.1/1415.
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Thesis (PhD (Medicine. Internal Medicine))--Stellenbosch University, 2008.Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease in Western countries, extending from steatosis (FLD) to steatohepatitis (NASH). Differentiation between NASH and nonprogressive NAFLD is difficult on clinical grounds therefore a need exists to identify reliable biomarkers of disease progression. The aims of the study were 1) to describe the disease profile of NAFLD/NASH in South African patients of the Western Cape, 2) to investigate the metabolic derangements associated with this condition, including insulin resistance, lipid abnormalities and liver fibrogenesis, and 3) to assess the possible involvement of candidate genes in relation to the disease phenotype in the patient cohort. A total of 233 patients (73% female) were enrolled in this study, consisting of 69% Cape Coloured, 25% Caucasian, 5% Black and 1% Asian individuals. All subjects were obese or overweight based on the assessment of body mass index (BMI). Screening for NAFLD identified 182 patients (87%) with ultrasonographical evidence of fatty infiltration and/or hepatomegaly. Liver biopsies were performed on patients with persistently abnormal liver functions and/or hepatomegaly. NAFLD was confirmed histologically in 111 patients of whom 36% had NASH and 17% advanced liver fibrosis. None of the Black patients had advanced fibrosis.
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Gibson, Philippa S. "Characterisation of the role of vitamin D in paediatric non-alcoholic fatty liver disease." Thesis, University of Surrey, 2017. http://epubs.surrey.ac.uk/813394/.
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Previous research has suggested a role for vitamin D in non-alcoholic fatty liver disease (NAFLD) pathogenesis. Several observational studies have observed low vitamin D status (25OHD) with poorer histological findings. The principal aims of this study were to assess diet and lifestyle, 25OHD status, gene variants in vitamin D metabolism in UK children, and separately examine the effect of vitamin D in an in vitro NAFLD model. Dietary results from the case control study (n=32) indicated vitamin D intakes of paediatric patient with biopsy-proven NAFLD and ultrasound-cleared obese patients were 1.7μg/day and 3.5μg/day, respectively, well below the new UK recommendation. Children failed to meet current UK government recommendations for physical activity. In our UK paediatric biopsy-proven NAFLD cohort (n=103), the majority of patients presented with deficient (< 25nmol/L, 25.5%) or insufficient (< 50nmol/L, 80.8%) mean serum 25OHD levels. Furthermore, patients had significantly lower 25OHD levels during winter months in comparison to summer (p=0.0001) and autumn (p=0.0026), while 25OHD levels were non-significantly lower in NASH compared to non-NASH patients (p=0.0576). We observed that single nucleotide polymorphisms (SNPs) involved in vitamin D metabolism were associated with poorer liver histology grading; specifically, three SNPs were associated with increased steatosis and one with increased inflammation score in Caucasian patients. Finally, LX-2 cells, an immortalised human hepatic stellate cell line, demonstrated significantly reduced cell proliferation (p=0.0005) with increasing doses of 1α,25(OH)2D3 after 10 days of incubation in clonogenic assays. In conclusion, we found that NAFLD children have extremely low levels of 25OHD throughout the year, with little dietary contribution. In addition, several vitamin D related SNPs were associated with poorer histological findings. These novel data suggest an important role for vitamin D in the pathogenesis and progression of NAFLD in a paediatric population.
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Anderson, Emma Louise. "The prevalence and determinants of non-alcoholic fatty liver disease in childhood and adolescence." Thesis, University of Bristol, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.684360.
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USS dataset and n=3 ,059 in the blood-based outcomes dataset). For example, the odds of USS liver fat per 100 kcal increase in energy intake at age 3 years were 1.79 (95% CIL 1.14 to 2.79). Associations of absolute macronutrient intake with the liver outcomes were inconsistent, and attenuated to the null after adjustment for total energy intake. Physical activity at ages 12 and 14 years was inversely related to risk of NAFLD in adolescence (n=I,292 in the USS dataset and n=2,612 in the blood-based outcomes dataset), for example the odds of liver fat per 15 minute increase in time spent in moderate to vigorous physical activity at age 12 was 0.55 (95%CI: 0.32 to 0.94). The majority of these observed associations attenuated towards the null upon adjustment for fat mass at the time the liver outcomes were assessed, suggesting that these associations may be, in part, mediated by adiposity in adolescence. These results suggest that risk of NAFLD is common in children and adolescents and that risk of NAFLD is affected by modifiable exposures throughout infancy, childhood and early adolescence. Public health initiatives aimed at promoting healthy growth and adiposity gain from infancy, through a healthy diet and physical activity, are warranted for the prevention of NAFLD.
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Zou, Xiantong. "The role of 11β-hydroxysteroid dehydrogenase type 1 in liver fibrosis and inflammation in non-alcoholic fatty liver disease." Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/18748.
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Non-alcoholic fatty liver disease (NAFLD) is a worldwide health problem which includes steatosis (triglyceride accumulation alone), non-alcoholic steatohepatitis (NASH, with liver inflammation), fibrosis, cirrhosis and hepatocellular carcinoma. Liver fibrosis, which is a reversible response, is the final phase of most chronic liver disease and is characterized by accumulation of extracellular matrix (ECM) from activated hepatic stellate cells (HSCs). Glucocorticoids (GCs) regulate many aspects of metabolism involved in NAFLD. Also, GCs limit HSC activation in vitro. Tissue GC levels are regulated by 11β- hydroxysteroid dehydrogenase-1 (11β-HSD1) which converts inactive 11- dehydrocorticosterone (DHC) into active corticosterone. Previous studies demonstrate that 11β-HSD1 deficiency improves fatty liver in obesity models, but the role of 11β-HSD1 in mechanisms involved in the progression and/or resolution of hepatic injury is largely unknown. I hypothesized that 11β-HSD1 modulates fibrotic and inflammatory responses during hepatic injury and/or the resolution phase. First I sought to address if the levels of 11β-HSD1 during different models of liver injury are dysregulated. In mice, 11β-HSD1 was down-regulated in choline deficient diet (CDD) induced steatosis, methionine and choline deficient diet (MCDD) induced NASH, carbon tetrachloride (CCL4) induced liver fibrosis and thioacetamide (TAA) induced liver fibrosis. In CCL4 injured livers, the down regulation of 11β- HSD1 was observed around the scar area. To test if 11β-HSD1 plays a key role in modulating liver inflammation and fibrosis responses in NAFLD and liver fibrosis I used initially11β-HSD1 knockout (KO) mice. 11β-HSD1 KO showed higher HSC activation only in the High fat feeding model but not in CDD and MCDD models. In the CCL4 injury model, despite reduced hepatocellular injury, 11β-HSD1 KO mice showed enhanced collagen deposition during peak injury and increased fibrotic gene expression during the early resolution phase although unaltered inflammatory markers during both peak injury and resolution. To further dissect cell-specificity on the effect of 11β-HSD1, I repeated the CCL4-injury model using the hepatocyte-specific 11β-HSD1 KO (Alb-HSD1). Alb-HSD1 mice did not show increased susceptibility to fibrosis compared to control littermates suggesting that the 11β- HSD1 possibly modulates fibrotic response by affecting HSC function. To mechanistically address how GCs inhibit HSC activation in vitro I studied the effects of 11β-HSD1 on HSC in vitro. 11β-HSD1 expression was down-regulated during ‘spontaneous’ HSC activation, and 11β-HSD1 deficiency enhanced susceptibility to activation. The GC (11-DHC)’s inhibitory effect on HSC activation was reversed by 11β-HSD1 inhibition. Finally, to address the clinical relevance of 11β-HSD1 in hepatic injury and/or resolution a selective 11β-HSD1 inhibitor, UE2316, was used. UE2316 induced a pro-fibrotic phenotype in ob/ob mice and CCL4-treated C57BL/6 mice, but had no effect when administered only during injury resolution. In conclusion, 11β-HSD1 deficiency causes increased activation of HSCs following diet and chemical injury and promotes liver fibrosis. Effects of 11β-HSD1 inhibitors, which are a potential treatment for metabolic syndrome, are perhaps offset by adverse outcomes in liver.
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MacFarlane, David Peter. "Factors determining the progression of nonalcoholic fatty liver disease : the role of abnormal fatty acid and glucocorticoid metabolism." Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/5914.
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Obesity and insulin resistance are associated with a constellation of features including hypertension, dyslipidaemia, type 2 diabetes, and premature cardiovascular disease, collectively termed the metabolic syndrome. Non-alcoholic fatty liver disease (NAFLD) represents the hepatic component of this syndrome, incorporating a spectrum of liver disease with increasing morbidity and mortality, from simple steatosis, to non-alcoholic steatohepatitis (or NASH), fibrosis, cirrhosis and ultimately hepatocellular carcinoma. However, factors influencing this progression are incompletely understood. In this thesis I sought to investigate pathways which promote hepatic inflammation and fibrosis by studying two contrasting dietary models of NAFLD in mice in which the risk of hepatic inflammation, insulin resistance and fibrosis differ; namely the methionine and choline deficient diet (MCDD) which induces steatohepatitis, hepatic insulin resistance, and weight loss, and the choline deficient diet (CDD) which may be protected from insulin resistance, and leads to steatosis without inflammation or weight loss. I investigated the possible molecular mechanisms underlying these differences, and whether they influenced progression to hepatic fibrosis induced by carbon tetrachloride (CCl4).
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Lee, Matthew L., and Jonathan M. Peterson. "Ethanol Disrupts Metabolic Signaling in Liver Cells." Digital Commons @ East Tennessee State University, 2014. https://dc.etsu.edu/etsu-works/69.
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Alcohol abuse is the third leading cause of preventable death in the United States. Excessive intake of alcohol can result to alcoholic fatty liver disease, the number one cause of live related mortalities in the US. The outlining purpose for this project is to determine the alcohol-induced changes in the liver cell protein signaling. For this project, we treated H4IIE rat hepatoma cells (with 100 and 200 mM ethanol overnight). H4IIE cells were chosen because they are a commonly used liver cell culture line that maintains characteristics of intact liver cells. After treatment we collected and prepared the cells for protein signaling analysis, using standard western blotting procedure. A western blot detects relative quantity of proteins in a sample. Briefly, protein samples are separated by size through electrophoresis, smaller proteins move faster through the gel so that the larger proteins are toward the top and smaller towards the bottom. The proteins are then transferred to a nitrocellulose membrane and protein concentration is detected by chemiluminescence. We chose to examine the effects of ethanol on the activation of the key regulator of metabolic signaling, Protein Kinase B/Akt (Akt). Based on our results, ethanol has no effect on the total amount of Akt in the H4IIE liver cells. However, ethanol significantly attenuates insulin-induced activation of Akt in a dose-dependent manner, as seen by a reduction in the amount of phosphorylated Akt. Therefore, we conclude that treatments that increase Akt activation may be a viable option for the treatment of alcoholic fatty liver disease.
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Jarrar, Mohammed Hussein. "Comparative profiling of circulatory levels of adipokines and cytokines in patients with various types of non alcoholic fatty liver disease." Fairfax, VA : George Mason University, 2007. http://hdl.handle.net/1920/2927.
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Thesis (Ph. D.)--George Mason University, 2007.Title from PDF t.p. (viewed Jan. 18, 2008). Thesis director: Ancha Baranova Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biosciences. Vita: p. 213 Includes bibliographical references (p. 188-212). Also available in print.
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Mouralidarane, A. C. "The role of developmental programming in the pathogenesis of non-alcoholic fatty liver disease (NAFLD)." Thesis, University College London (University of London), 2012. http://discovery.ucl.ac.uk/1354935/.
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Obesity induced, non-alcoholic fatty liver disease (NAFLD), describes the spectrum from steatosis-to-cirrhosis. NAFLD is now the commonest cause of chronic liver disease in affluent populations. Its prevalence is increasing in tandem with rising obesity rates. However, given the exponential rise in obesity and NAFLD disease prevalence, availability of cheap energy dense foods may not alone be the sole determinant of these rising rates: maternal obesity – through developmental programming - may also be involved. A growing body of epidemiological evidence suggests that perinatal factors may contribute to chronic disease in adulthood via programming. Programming is the process whereby an insult/stimulus during a critical period of development induces permanent structural and/or physiological changes. The role of developmental programming in NAFLD is unknown. The aims, therefore were to determine if maternal obesity during gestation and/or lactation transmits a predisposition to NAFLD in offspring, to evaluate the natural progression of such programmed disease, to examine the relative contributions of maternal obesity and the post-natal environment on offspring NAFLD and to investigate the mechanisms therein. Using a rodent diet induced obesity-programming model, our initial studies confirmed that maternal obesity, through developmental programming, was indeed involved in the pathogenesis of NAFLD with the lactation period most susceptible to these programming effects. Moreover, there was an interaction between in utero exposure to an obesogenic environment and a post-weaning obesogenic environment to cause exacerbated offspring NAFLD. Mechanistically, perturbed hepatic innate immune function and disrupted peripheral circadian rhythms were observed in offspring with NAFLD programmed by maternal obesity. Finally, these results also provide a novel and uniquely pathophysiologically relevant model of NAFLD.
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Williamson, Rachel MacLeod. "Prevalence, risk factors and sequelae of non-alcoholic fatty liver disease in Type 2 diabetes." Thesis, University of Edinburgh, 2013. http://hdl.handle.net/1842/25315.
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Type 2 diabetes is an established risk factor for non-alcoholic fatty liver disease (NAFLD). Despite this, there are few data investigating NAFLD within large populations of people with Type 2 diabetes. In the initial chapters of this thesis NAFLD is defined and the pathological processes linking it to Type 2 diabetes are described. The epidemiological evidence that underpins current understanding of prevalence, risk factors and progression of the condition is reviewed in detail. Subsequent chapters describe research undertaken within the Edinburgh Type 2 Diabetes Study on the epidemiology of NAFLD in this population. The prevalence of NAFLD was determined within 939 subjects, aged 61 - 76 years, with well-characterised Type 2 diabetes. NAFLD was defined by the presence of ultrasounddiagnosed steatosis with detailed exclusion of secondary causes for liver disease. Ultrasound gradings were validated in a subgroup of 58 participants using 1Fi magnetic resonance spectroscopy, the non-invasive gold-standard method for hepatic lipid quantification, and intra- and inter-observer variability in ultrasound grading was calculated. The final prevalence of NAFLD, 42.6%, was higher than in the general population, but lower than in the few studies that have been performed in populations with Type 2 diabetes. It is likely that this was due to comprehensive screening for secondary causes of liver disease and validation of the ultrasound measure which resulted in re-categorisation as "normal" subjects initially graded as having mild steatosis. Independent predictors of NAFLD were diabetes variables or components of the metabolic syndrome. The utility of conventional "liver function tests" in detecting hepatic steatosis and NAFLD was examined. Although liver enzyme levels (alanine aminotransferase, aspartate aminotransferase and gamma-glutamyltransferase) were significantly higher in participants with hepatic steatosis compared with those with normal liver on ultrasound, values remained within the normal range in the majority of cases. The negative predictive values of normal levels were therefore low, calling into question their utility as screening tests for liver disease in the diabetic population. The prevalence of advanced liver disease had not previously been studied in a population with Type 2 diabetes, and was investigated in our population using surrogate markers of hepatic fibrosis. Hyaluronic acid (HA) levels were significantly elevated in 5.7% of subjects and 0.4% had ultrasound-diagnosed cirrhosis. Hepatocellular carcinoma was detected in 0.2% of participants. Liver enzyme markers were poorly predictive of high HA levels. Clinical risk scores identified a large proportion of subjects as potentially having severe fibrosis, but these scores have not previously been validated in populations with Type 2 diabetes and therefore have to be interpreted with caution. NAFLD has previously been shown to be predictive of cardiovascular disease in the context of Type 2 diabetes, but mechanisms underlying this have not been fully elucidated. In the current study the association of hepatic steatosis and NAFLD with non-classical cardiovascular risk factors - clot formation and lysis dynamics, prothrombotic mediators and markers of inflammation - was investigated. NAFLD was significantly associated with a longer clot lysis time and higher levels of complement C3 and plasminogen activator inhibitor type 1. Following adjustment for these prothrombotic compounds, the association of NAFLD and clot lysis time was lost, and it is therefore hypothesised that NAFLD may influence clot lysis time via increased production of these mediators.
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Ashfaq-Khan, Muhammad [Verfasser]. "Dietary wheat amylase trypsin inhibitors worsen chronic liver disease in preclinical models of non-alcoholic fatty liver disease and liver fibrosis / Muhammad Ashfaq-Khan." Mainz : Universitätsbibliothek Mainz, 2018. http://d-nb.info/1173844449/34.
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Jolin-Rodrigue, Gabriel. "Effects of Imidacloprid in the Development of Non-Alcoholic Fatty Liver Disease and the Effects of Exercise Training." Thesis, Université d'Ottawa / University of Ottawa, 2019. http://hdl.handle.net/10393/38900.
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The non-alcoholic fatty liver disease (NAFLD) is the most common liver pathology in developed countries with an estimated prevalence of 20 to 30% in the American population. A typically benign and asymptomatic pathology, NAFLD is characterized by hepatic steatosis and abnormal levels of hepatic enzymes stemming from an increase in circulating free fatty acids originating from white adipose tissue lipolysis, an increased de novo lipogenesis, reduced fatty acid oxidation and decreased hepatic triglycerides secretion, all within an insulin resistance context. NAFLD has the potential to progress to the non-alcoholic steatohepatitis (NASH), a condition marked by inflammation, advanced oxidative stress and fibrosis. NASH is expected to be the leading cause of liver transplant by 2020 due to its complications (i.e.: cirrhosis, hepatocellular carcinoma and liver failure). Various xenobiotics such as pesticides have been shown to promote the apparition and development of NAFLD. Of interest to this study is the neonicotinoid imidacloprid, more contemporarily known for its suspected role in the colony collapse disorder of various anthophilae species. Imidacloprid has been shown to induce hepatic oxidative stress in rats, a significant factor in the development of NAFLD and its progression to NASH. Lifestyle modifications, namely physical exercise, is a current treatment which has been proven beneficial to prevent and treat NAFLD by reducing hepatic steatosis, oxidative stress and improving insulin sensitivity. The role of any neonicotinoid on the development of NAFLD has yet to be examine and few have looked at the role of exercise in the treatment of NAFLD brought about by pesticide contamination.
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Perchet, Thibaut. "Roles of hepatic group 1 ILC during the early stages of non-alcoholic fatty liver diseases." Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCC314.
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Les maladies du foies non-alcoholiques (NAFLD) représentent un large spectre de pathologies qui comprennent la stéatose ou la stéatohepatite non alcoolique (NASH). Avec un nombre de patients diagnostiqué en constante augmentation, les NAFLD sont devenues un problème majeur de santé publique dans le monde. Un hypothése de « multiples hits » à été décrite pour regrouper l’ensemble des dérégulations métaboliques associées à la transition de la stéatose vers la NASH. Cette étape est critique au cours de la pathogénèse des NAFLD. En effet dans le cas où la NASH n’est pas prise en charge, elle peut se transformer en une fibrose ou une cirrhose et finalement en un cancer hepatocellulaire (CHC). Ainsi, l’analyse des évènements précoces au cours des NAFLD sont essentiels pour comprendre son évolution vers des pathologies plus dommageables. Dans le foie, plusieurs populations de cellules sont impliquées dans le métabolisme et les fonctions hépatiques ainsi que dans la surveillance immunitaire. Parmi celles ci, le groupe 1 ILC est enrichie dans le foie et peut rapidement induire une réponse immunitaire en produisant des cytokines ou en induisant la mort cellulaire. Le groupe 1 ILC hépatique est composé des cellules NK (Natural Killers) et des ILC1 (Cellules Lymphoïdes Innées de type 1), deux populations de cellules qui partagent un phénotype semblable. Cependant, elles forment bien deux lignages distincts avec des caractéristiques uniques. Nous proposons donc d ‘étudier le(s) role(s) des cellules NK et des ILC1 au cours des étapes précoces des NAFLD.Dans cette étude, nous avons démontré les cellules NK et les ILC1 subissent des modifications hétérogènes au cours des étapes précoces des NAFLD. Alors que les ILC1 présentent une diminution de leurs marqueurs d’activation et d’inhibition et de production de granzyme B, nous détectons une accumulation de cellules NK produisant de l’interféron gamma (IFNg). Ces modifications sont induites rapidement au cours de la stéatose et sont même antérieures au recrutement et à l’activation d’autres cellules immunitaires du foie. Nous soulignons également l’importance du système immunitaire intestinal au cours de l’inflammation hépatique et proposons que la lamina propria de l’intestin puisse servir de réservoir de cellules NK au cours de ce processus. Finalement, nous avons démontré que l’IFNg, secrétée entre autre par les cellules NK induise des dommages au cours de la stéatose mais n’est pas impliquée dans le recrutement ou les modifications observées sur le groupe 1 ILC. Cette étude apporte de nouveaux éléments sur les étapes précoces des NAFLD ainsi que le rôle du groupe 1 ILC au cours de l’inflammation hépatique. Cette étude souligne également l’importance de la distinction entre les cellules NK et les ILC1 au cours des pathologies du foieNon-alcoholic fatty liver diseases (NAFLD) is a spectrum of liver pathologies that encompass diseases such as steatosis or non-alcoholic steatohepatitis (NASH). With a constant increase of patients diagnosed, NAFLD is becoming a major concern of public health worldwide. A “multiple hits” hypothesis has been described to regroup the metabolic disorders that are associated with the transition from steatosis to NASH. This transition is a critical step during NAFLD pathogenesis as untreated NASH can further develop into fibrosis, cirrhosis and ultimately to hepatocellular carcinoma (HCC). Thus, the analysis of early events occurring during during NAFLD is critical to understand its evolution to more severe pathologies. In the liver, diverse cell populations are involved in hepatic metabolism, function and immune surveillance. Among them, the group 1 ILC is enriched in the liver and can quickly induce an immune response by producing cytokines or inducing cell death. Hepatic group 1 ILC is composed of Natural Killer (NK) cells and Innate Lymphoid Cells 1 (ILC1), two cell populations that share a similar phenotype. Nevertheless they constitute two distinct cell lineages that have unique features. Here we propose to study the roles of NK cells and ILC1 during the early stages of NAFLD.In this work, we demonstrated that NK cells and ILC1 diverge in phenotype and function during the early stages of NAFLD pathogenesis. While ILC1 showed a down-regulation of inhibitory markers and down-regulation of granzyme B, we detected an increase of interferon gamma (IFNg) secreting NK cells. These modifications were found shortly after the induction of steatosis and preceded other hepatic immune cell recruitment or activation. Our work highlighted the role of the immune intestinal populations during liver inflammation and identified the intestinal lamina propria as a potential source of NK cells during this process. Finally, we demonstrated that IFNg is inducing liver damage, but is not involved in hepatic group 1 ILC recruitment or modification in our model of steatosis.This study brings new insights on the early events of NAFLD and the role of hepatic group 1 ILC during liver inflammation. It also underlines the importance of distinguishing the roles of NK cells and ILC1 in liver pathologies
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Lin, Hui-Ting, and 林惠婷. "The Extracts of Mulberry Leaves inhibits Non-Alcoholic Fatty Liver Disease and Alcoholic Fatty Liver Disease." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/52558303651182285354.
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碩士中山醫學大學
生化暨生物科技研究所
102
Non-alcoholic fatty liver disease (NAFLD), a leading cause of liver damage, comprises of a spectrum of liver abnormalities including the early fat deposition in the liver (hepatic steatosis) and advanced nonalcoholic steatohepatitis (NASH). In addition, alcoholic liver disease (ALD) also lead to similar liver syndrome with NASH.In previous studies, mulberry leaves had been demonstrated to possess anti-oxidantant promoting effects. In this study, we have examined the effect of water extracts of mulberry leaves (MLE) on HFD-induced hepatic steatosis in rats. We used two animal models to do our research: NASH and ALD models. The rats were fed either a rodent normal chow, chow containing high-fat diet (HFD), or HFD containing 0.5% or 1% and 2% MLE in the diet for 10 weeks. Moreover, we first fed the HFD diet for 4 weeks to induce hepatic steatosis, then treated with MLE (0.5% or 1% and 2% in the diet) in the HFD diet for 6 weeks. In ALD model, we fed Lieber-DeCarli alcohol liquid feed for 8 weeks. We assayed antioxidant enzyme activity, such as SOD, catalase, GSH peroxidase. Furthermore, we also used the ELISA kits to measure the inflammatory factors, such as IL-6, TNF-α and the fat-relative factors, as adiponectin, leptin. Our data indicated that both NASH and ALD model are inclusion of 0.5%, 1% and 2% MLE in the HFD diet decreased liver fat content, liver weight, hepatic oxidative products, and prevented hepatic steatosis significantly. In serum, the AST, ALT and total triglyceride, total cholesterol decreased significantly in treating MLE group. MLE increased anti-oxidant enzyme activities in liver of HFD-induced rats. We also found that inflammatory factors TNF-d and the fat-relative factors, such as adiponectin, leptin, reduced in the treating MLE groups. These findings suggested that MLE effectively prevented and caused the regression of experimental hepatic steatosis. In the future, we could find the way to do more research about finding more effective compounds from mulberry leaves so that we would have more solution about treating liver disease.
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Fox, Ryan. "Vitamin D to reduce liver fibrosis in non-alcoholic fatty liver disease." Thesis, 2017. https://hdl.handle.net/2144/26591.
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BACKGROUND: As the prevalence of metabolic risk factors in the American population has increased over time, so too has the diagnoses of non-alcoholic fatty liver disease (NAFLD). Within this spectrum of disease lies the potential for silent progression towards cirrhosis, leaving the patient with few options for treatment. Currently, the standard of care remains counseling on diet and exercise with the goal of reversing disease progression by addressing the underlying risk factors.
LITERATURE REVIEW: Recent studies have shown that a correlation exists between low levels of serum 25-hydroxyvitamin D and hepatic injury from NAFLD. This has become an active area of research, due in part to the anti-inflammatory and immunoregulatory properties of vitamin D. The prospect of a simple and cost effective intervention that can exert its effects on the mechanisms behind the development of NAFLD is interesting and warrants further research.
PROPOSED PROJECT: This proposal is for a double-blind, randomized, experimental study of vitamin D3 (cholecalciferol) versus placebo in a patient population of those with both clinically proven NAFLD and concomitant vitamin D deficiency. Liver fibrosis will be measured and staged with the use of FibroScan elastography. The statistical analysis thereafter will determine if a clinically significant reduction in hepatic fibrosis exists, compared with the results of the placebo group.
CONCLUSIONS/SIGNIFICANCE: Should vitamin D prove to be an effective treatment option in reversing the progression of NAFLD, clinicians would be equipped with a simple and safe tool to augment their management of the patient. For those that experience barriers (i.e. lower socioeconomic status, other comorbidities, etc.) preventing them from improving diet and exercise, vitamin D would serve as an alternative therapy to aid in reducing their disease burden. Easier methods to treat their disease now projects improved quality of life years later.
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Lin, Ya-Lin, and 林雅琳. "Proteomic Analysis of Non-Alcoholic Fatty Liver of Hamster." Thesis, 2013. http://ndltd.ncl.edu.tw/handle/83789661696295473637.
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碩士實踐大學
食品營養與保健生技學系碩士班
101
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease. It may result from abnormal lipid metabolism, decreased β-oxidation, and increased oxidative stress. This study aimed to explore the changes in proteomics of nonalcoholic fatty liver. Eight-week old male Syrian hamsters were maintained on either control diet or high-fat diet (0.2% cholesterol + 20% fat) for 8 weeks. Liver proteins were fractionated by electrophoresis, digested by trypsin, and then separated by nano-LC/MS/MS. TurboSequest algorithm was used to identify peptide sequence against the hamster database in Universal Proteins Resource Knowledgebase. Six hundred and ninety-three proteins were identified in the livers and 88 of them were expressed differently in high-fat group (p<0.05). Acyl-coenzyme A synthase medium-chain family member 2A (ACSM2A), mitochondrial trifunctional protein alpha subunit, MTPα), and acyl-CoA dehydrogenase short/branched chain, ACADSB) which involve in β-oxidation were down-regulated in high-fat group (p<0.05). The phase II enzyme glutathione S-transferase, GSTA3) was also down-regulated by high-fat diet. However, xanthine dehydrogenase (XDH) which plays a role in uric acid synthesis was up-regulated in high-fat group. The results of serum analysis showed that animals in high-fat group had significantly (p<0.05) higher levels of triglyceride, cholesterol, and uric acid. Activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in serum were also significantly (p<0.05) higher in animals kept in high-fat diet. Keywords: Nonalcoholic fatty liver , high-fat diet, proteomics, hamster
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Magalhães, Nuno Manuel Queiroz Pimenta de. "Body composition in non-alcoholic fatty liver disease patients." Doctoral thesis, 2014. http://hdl.handle.net/10400.5/7450.
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Doutoramento em Motricidade Humana, na especialidade de Actividade Física e SaúdeThe present thesis includes five original studies focusing on body composition (BC) in non-alcoholic fatty liver disease (NAFLD) patients, mainly in a clinical perspective, directed to clinical practice. The first study of this thesis aimed at analyzing the relation between body fat (BF) content and distribution, as assessed by dual energy x-ray absorptiometry (DXA), and cardiac autonomic control, more specifically with heart rate recovery after a maximal exercise test, which is an indirect clinical marker of parasympathetic reactivation, also known to be a strong risk factor for overall and cardiac mortality. The second study focused on the utility of waist circumference (WC) measurement, as a predictor of both BF content and distribution, and also on the comparison of different WC measurement protocols based on biological criteria, protocols’ precision and practical criteria, aiming to identify a preferential measurement protocol to be used in NAFLD patients. The third and fourth studies focused on the influence of using different WC measurement protocols in the relation of both waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR) with BF content and distribution, as assessed by DXA, and aimed to identity a preferable measurement protocol. The fifth study focused on body indexes and circumferences usefulness as surrogates of BF content and distribution and aimed at identifying if there is a preferential clinical predictor of both BF content and distribution, as compared to the commonly used body mass index, in NAFLD patients. The results obtained confirmed the strong relation between BC and cardiac autonomic control and showed that BF distribution is more important than BF content in explaining cardiac autonomic control variation. It was also possible to conclude that WC measured just above the iliac crest seem preferable to be used in NAFLD patients, either singly or included in body indexes such as WHR or WHtR, mostly due to practical criteria but also because of it strong correlation with both BF content and distribution. WHtR appears to be the best BF content and distribution surrogate to be used in clinical practice with NAFLD patients. WC alone is a good practical alternative, when simplicity and time saving are important instrument/method selection criteria.
RESUMO: A presente tese integra cinco investigações originais que se centram no estudo da composição corporal (CC) em pacientes com doença do fígado gordo não-alcoólico (DFGNA), numa perspetiva eminentemente clínica e direcionada para a prática. Um primeiro estudo visou analisar a relação da quantidade e distribuição da massa gorda corporal (MG), avaliada por densitometria por raio-X de dupla energia (DXA), com o controlo autonómico cardíaco, mais especificamente com um indicador indireto da reativação do sistema nervoso parassimpático, que é a frequência cardíaca de recuperação após um esforço máximo, que também é um forte fator de risco para mortalidade. O segundo estudo visou avaliar a utilidade da medição do perímetro da cintura, isoladamente, como preditor da quantidade e distribuição de MG, em pacientes com DFGNA, e comparar os resultados e os procedimentos da medição do perímetro da cintura realizada segundo diferentes protocolos de medição de modo a identificar um protocolo preferencial. O terceiro e quarto estudo pretenderam avaliar o impacto da utilização do perímetro da cintura obtido segundo diferentes protocolos de medição na performance da razão cintura/anca e da razão cintura/altura, enquanto indicadores clínicos, duplamente indiretos, de quantidade e distribuição de MG. O quinto e último estudo deste trabalho teve como objetivo avaliar a relação de perímetros e índices corporais com a quantidade e distribuição de MG, em pacientes com DFGNA, e procurou identificar a existência de alternativas preferenciais à utilização do índice de massa corporal. Os resultados encontrados no presente trabalho permitem confirmar que a CC está fortemente relacionada com o controlo autonómico cardíaco, em pacientes com DFGNA, e que, nessa relação, a distribuição de MG parece ser mais determinante do que a sua quantidade absoluta e relativa. Também foi possível concluir que o perímetro da cintura medido imediatamente acima da crista ilíaca parece ser a melhor metodologia para ser utilizada com esta população, sobretudo por razões de ordem prática, mas também pelo seu desempenho na relação com quantidade e distribuição de MG, quer quando utilizado isoladamente como quando integrado em índices corporais, como a razão cintura/ anca ou a razão cintura/ altura. A razão cintura/altura parece ser a melhor alternativa para ser usada como preditor da quantidade e distribuição de MG em pacientes DFGNA, sendo que o perímetro da cintura também é uma boa alternativa sobretudo por razões de ordem prática.
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Shu-Lin and 劉淑玲. "Explore on Serum Biomarkers of Alcoholic Fatty Liver and HCV-induced Liver Fibrosis." Thesis, 2012. http://ndltd.ncl.edu.tw/handle/5bh3j9.
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博士中山醫學大學
生化暨生物科技研究所
100
Excessive consumption of alcohol contributes to alcoholic liver disease. Fatty liver is the early stage of alcohol-related liver disease. The aim of this study was to search for specific serological biomarkers of alcoholic fatty liver (AFL). Search for early protein biomarkers will contribute to the prevention of alcoholic liver disease have a follow-up of liver lesions for early detection and treatment. Otherwise, Hepatic inflammation is the stimulator to activate hepatic stellate cells (HSCs) and triggers fibrogenesis. , although many biomarkers have been reported associated with liver fibrosis. In the past, the discovery of serological biomarkers was limited due to the abundant amount of albumin and IgG in serum, which would decrease the accuracy in analytical experiments. There are two purposes of this thesis research , One for use two-dimensional differential gel electrophoresis and mass spectrometer search for new serum biomarkers of alcoholic fatty liver, and also using Bio-Plex suspension array system based on flexible Multi-Analyte Profiling (xMAP ) technique to explore whether cytokines can be Biomarkers of liver fibrosis. First, to generate animals with AFL, non-AFL (NAFL), and liver fibrosis. Wistar rats were orally fed alcohol, fructose and thioacetamide (TAA)-containing drinking water, respectively. Eight differential putative biomarkers were identified, and the two most differentiated proteins, including upregulated C-reactive protein (CRP) and downregulated haptoglobin (Hp). Western blotting validated that CRP was dramatically higher in the serum of AFL compared to healthy controls and other animals with liver disease of NAFL or liver fibrosis (p < 0.05). Moreover, we found that CRP and Hp were both lower in liver fibrosis of TAA-induced rats and clinical hepatitis C virus-infected patients compared to healthy controls, suggesting that CRP and Hp are reliable biomarkers of liver fibrosis to assist the accuracy of clinical diagnosis. Otherwide, the xMAP and commercial cytokines 27- and 23-panels were used to search for putative serum biomarkers of liver fibrosis. Totally 50 cytokines were screened using flexible multi-analyte profiling to discover differential biomarkers. Finally, levels of protein expressions of individual stages of liver fibrosis were measured. Four serum cytokines, including IFN-α2 (p=0.023), GRO-α (p=0.013), SCF (p=0.047) and SDF-1α (p=0.024), were identified and they were increased from F1 to F4 stage in hepatitis C virus (HCV) infected patients. This study reveals the relationship between cytokines and liver fibrosis, and demonstrated that IFN-α2, GRO-α, SCF and SDF-1α may be used as biomarkers to predict liver fibrosis.
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Mouzaki, Marialena. "Assessment of Intestinal Microbiota in Non-alcoholic Fatty Liver Disease." Thesis, 2012. http://hdl.handle.net/1807/33467.
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Non-alcoholic fatty liver disease (NAFLD) includes simple hepatic steatosis (SS) and non-alcoholic steatohepatitis (NASH). NAFLD is tightly linked to obesity and is thought to be secondary to various noxious signals, some of which may originate from the intestinal microbiota (IM). Despite a growing body of evidence supporting a link between obesity and altered IM, there are no studies assessing the IM of patients with NAFLD. In this cross-sectional study we aimed at comparing fecal levels of total bacteria, Bacteroidetes, C. coccoides, C. leptum, Bifidobacteria, E. coli, and Archaea between healthy controls (HC) and patients with SS or NASH. We found higher C. coccoides levels in NASH compared to SS and lower percentage Bacteroidetes in NASH compared to SS and HC. Controlling for body mass index and fat intake we found an association between presence of NASH and percentage Bacteroidetes. The latter inversely correlated with insulin resistance.
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Lin, Jhih-Huei, and 林智暉. "Quantitative Ultrasound for Non-Alcoholic Fatty Liver Diagnosis: Feasibility Study." Thesis, 2017. http://ndltd.ncl.edu.tw/handle/6x639a.
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Liu, Chun-Ting, and 劉俊霆. "Metabolomics Study of Ginger Essential Oil against Alcoholic Fatty Liver." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/17374979932942865566.
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博士國立臺灣大學
食品科技研究所
102
Fatty liver is highly associated with hepatic cirrhosis, and liver cancer. The pathogenesis of fatty liver is mainly divided into two categories: non-alcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD). Alcoholic and non-alcoholic fatty livers could be induced by alcohol consumption, obesity and hyperlipidemia. Ginger has been reported to exhibit antioxidant potential and hepatoprotective activity. In present study, a mouse model for AFLD was developed and validated by employing male C57BL/6 (B6) mice with alcohol containing liquid diet (Lieber-DeCarli diet) ad libitum. In the treatment groups, ginger essential oil (GEO) and citral, one of the major active compounds in GEO, were administered orally every day for 4 weeks. Metabolites in serum and urine samples were profiled by ultra high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS). Serum biochemical analysis, liver antioxidant enzyme activity and histopathological evaluation, of GEO treated mice exhibited hepatoprotective activity on alcohol-induced fatty liver. Several metabolites involved in key biochemical pathways were identified to be implicated by AFLD after four weeks of alcohol administration, such as D-glucurono-6,3-lactone, glycerol-3-phosphate, pyruvic acid, lithocholic acid, 2-pyrocatechuic acid, prostaglandin E1, methionine, L-gulono-1,4-lactone, lactate in serum samples, and serine, allantoin, 5''-methylthioadenosine, taurine in urine samples. The metabolomics result indicated these metabolites were related to AFLD. These metabolites can be use as biomarker candidates for the healthy management and clinical application on AFLD.
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Sacramento, Ferreira Duarte Miguel. "Apoptosis and miRNAs in non-alcoholic fatty liver disease pathogenesis." Doctoral thesis, 2013. http://hdl.handle.net/10451/9334.
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Tese de doutoramento, Farmácia (Bioquímica), Universidade de Lisboa, Faculdade de Farmácia, 2013Fundação para a Ciência e a Tecnologia (FCT, SFRH/BD/60521/2009, PTDC/SAU-OSM/102099/2008, PTDC/SAU-OSM/100878/2008, PTDC/SAU-ORG/111930/2009,PEst-OE/SAU/UI4013/2011) e FEDER (Fundo Europeu de Desenvolvimento Regional)
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Lin, Yu-Cheng, and 林裕誠. "Genetic Influences in Non-alcoholic Fatty Liver Disease in Obese Children." Thesis, 2011. http://ndltd.ncl.edu.tw/handle/09080728651664528916.
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博士國立臺灣大學
臨床醫學研究所
99
Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of conditions ranging from simple hepatic steatosis to potentially fatal nonalcoholic steatohepatitis and cirrhosis. Concurrent with the epidemic of childhood obesity, pediatric NAFLD is a growing global problem. The pathogenesis of NAFLD is multifactorial; it is strongly associated with obesity and insulin resistance. Not all children with obesity will develop NAFLD, suggesting that genetic factors may contribute to the NAFLD susceptibility. NAFLD is a complex metabolic disease that is strongly associated with obesity and insulin resistance. Day and James proposed a two-hit hypothesis. Fat accumulation in the liver is the first hit. Additional hits, including oxidative stress, lipotoxicity, adipocytokines, etc., are potential mediators in inducing persistent liver injury. Candidate genes studied in our studies were selected based on the two-hit hypothesis. With regard to the genetic susceptibility to the first hit, PNPLA3 rs738409 single nucleotide polymorphism (SNP), causing a nonsynonymous sequence variation I148M, had a strong association with increased liver fat content in adults. In our study, we hypothesized that the presence of the PNPLA3 rs738409 G allele would increase the susceptibility of NAFLD in obese Taiwanese children. We recruited a total of 520 obese children aged 6-18 years. Their PNPLA3 rs738409 genotypes-CC, CG, or GG-were detected by the 5''-nuclease assay. The effects of the PNPLA3 rs738409 G allele on pediatric NAFLD were evaluated based on liver ultrasonography findings and mean serum alanine aminotransferase levels in these children. We found that NAFLD was present in 19.6% of the obese children. In comparison to the subjects with CC alleles, the risk of NAFLD was increased by 2.96-fold (95% confidence interval, 1.57-5.59, P = 0.0008) in the subjects with CG alleles and by 5.84-fold (95% confidence interval, 2.59-13.16; P < 0.0001) in those with GG alleles. Variant PNPLA3 rs738409 genotypes were associated with increases in mean serum alanine aminotransferase level of 4.77 IU/L (P = 0.0435) in subjects with CG alleles and of 10.86 IU/L (P < 0.0001) in those with GG alleles compared with subjects with CC alleles. In conclusion, the variant PNPLA3 rs738409 genotypes increased the risk of NAFLD in our population of obese Taiwanese children. The effect of the G allele on pediatric NAFLD followed a dominant genetic model. With regard to the genetic susceptibility to the second hit, oxidative stress plays an important role in the pathogenesis of NAFLD. Variants in the UGT1A1 gene contribute to increased bilirubin levels, and bilirubin can act as an antioxidant. In our study, we hypothesized that variant UGT1A1 genotypes would reduce the risk for NAFLD development. We recruited 234 obese children 6 to 13 years of age. NAFLD was determined through liver ultrasonography. The UGT1A1 genotypes UGT1A1*6 and UGT1A1*28 were detected. We assessed the effects of UGT1A1 genotypes on pediatric NAFLD. We found that in total, 12% of the obese children had NAFLD. The subjects with NAFLD had lower serum total bilirubin levels (0.25 ± 0.30 mg/dL) than did those without NAFLD (0.36 ± 0.38 mg/dL; P = 0.021). With conditioning on the effects of age- and gender-adjusted BMI, waist/hip ratio, and adiponectin levels, variant UGT1A1*6 genotypes were a protecting factor for NAFLD, with an estimated adjusted odds ratio (OR) of 0.31 [95% confidence interval (CI): 0.11-0.91; P = 0.033], but variant UGT1A1*28 genotypes were not significantly associated with the occurrence of NAFLD. In conclusion, variant UGT1A1*6 genotypes are associated with a lower risk of NAFLD in obese Taiwanese children. The UGT1A1 genotype is a new risk factor for pediatric NAFLD. The heritability of pediatric NAFLD, as estimated by family aggregation study, is high. We genotyped 24 selected SNPs in 11 NAFLD-related candidate genes which may be involved in the first hit or second hit on the pathogenesis of NAFLD . We examined the associations between SNPs and the risk of pediatric NAFLD in obese children with conditioning on the effect of PNPLA3 rs738409 polymorphism. We selected these 24 SNPs by a pathway-driven approach, including autophagy (ATG16L1, PIK3C3, IRGM), toll-like receptor (CD14, TOLLIP), inflammatory (TNF-α), fatty acid metabolism (PPARG, PPARGC1A), and adiponectin signaling (ADIPOQ, ADIPOR1, ADIPOR2) pathways. SNPs were chosen based on minor allele frequency higher than 5% among Han Chinese. NAFLD was determined by liver ultrasonography. Associations between SNPs and pediatric NAFLD were examined using multiple logistic regression models. We found that a total of 95 cases and 91 controls were studied. The two groups matched each other in terms of age, gender and body mass index. With conditioning on the effects of waist circumference, triglyceride, adiponectin and PNPLA3 rs738409 polymorphism, one PPARGC1A SNP (rs8192678) was significantly associated with an increased risk for pediatric NAFLD OR, 2.21; 95% CI, 1.04–4.69; P=0.0389) and one TNF-α SNP (rs1799964) was significantly associated with a decreased risk for pediatric NAFLD (OR, 0.49; 95% CI, 0.24–0.99; P=0.0487). We further genotyped all 520 participants and analyzed the effect of PPARGC1A rs8192678 SNP variants on pediatric NAFLD. With conditioning on the effects of gender, adujsted BMI, waist circumference, adiponectin and PNPLA3 rs738409 polymorphism, variant PPARGC1A rs819267 genotypes increased the risk for pediatric NAFLD by 90% (OR, 1.9; 95% CI, 1.02–3.57; P=0.045). In conclusion, the variant PPARGC1A rs8192678 and TNF-α rs1799964 genotypes significantly modified the risk of NAFLD independent of the effect of PNPLA3 rs738409 polymorphism in our population of obese Taiwanese children. Excessive cholesterol accumulation in the liver is involved in the deterioration of NAFLD. The underlying mechanism was unknown. We used an oleic acid-induced steatotic Huh7 cell model to investigate the changes in the expression levels of key cholesterol metabolism genes. We found that the mRNA expression of HMG-CoA reductase was increased by 19% in 0.5 mM oleic acid treated steatotic Huh7 cells (P = 0.024). HMG-CoA reductase is the rate-limiting key enzyme in the regulation of cholesterol biosynthesis in liver. We proved that the excessive cholesterol accumulation in the NAFLD liver is induced by increased expression of HMG-CoA reductase gene. Our results suggest that cholesterol is a possible lipid mediator linking the first hit and the second hit on the pahtogenesis of NAFLD. In summary, we focused on finding associations between pediatric NAFLD and variants in candidate genes encoding proteins involved in NAFLD pathogenesis. Our findings may contribute to the understanding of the genetic susceptibility to pediatric NAFLD. Considering the lack of data in Asian children, the results of our genetic association studies in obese Taiwanese children could be valuable for global comparisons with data from other ethnic groups, including Hispanic, African, and North American or European origin.
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Chi, Yu-Wen, and 杞玉雯. "Effect of shikonin on non-alcoholic fatty liver disease (NAFLD) cells." Thesis, 2017. http://ndltd.ncl.edu.tw/handle/bdv59g.
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