To see the other types of publications on this topic, follow the link: Liver Diseases, Alcoholic.
Dissertations / Theses on the topic 'Liver Diseases, Alcoholic'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 dissertations / theses for your research on the topic 'Liver Diseases, Alcoholic.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse dissertations / theses on a wide variety of disciplines and organise your bibliography correctly.
1
Stokkeland, Knut. "Studies on alcoholic liver disease /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-853-3/.
Full text
2
Owoseni, Seun Emmanuel. "The Study of Alcoholic Liver Diseases." Digital Commons @ East Tennessee State University, 2018. https://dc.etsu.edu/etd/3493.
Full textAbstract:
Excessive alcohol consumption is the primary contributing factor in the development of alcoholic liver diseases (ALD). Nicotine contained in tobacco is a major addictive alkaloid, which enhances the effects of ALDs. The major enzyme involved in nicotine metabolism is cytochrome P450 2A5 (CYP2A5) which is produced in the liver. Alcohol can stimulate the CYP2A5 enzyme. We utilized cyp2a5-/- knockout mice in this research to examine the effects of CYP2A5.
The cyp2a5-/- mice and wild-type (WT) mice were fed liquid ethanol diet with or without nicotine to induce ALD. Nicotine enhancing effects on ALD were observed in WT mice but not in cyp2a5-/- mice. Oxidative stress was stimulated by alcohol and further increased by nicotine in WT mice but not in cyp2a5-/-mice. Microsomal ROS production during microsomal metabolism of nicotine was increased in WT mice but not in cyp2a5-/-mice. These results suggest that nicotine enhances ALD is CYP2A5 dependent.
3
Fulham, Melissa A. "Characterization of Adipose Tissue Inflammation in Alcoholic Liver Disease." eScholarship@UMMS, 2011. http://escholarship.umassmed.edu/gsbs_diss/940.
Full textAbstract:
Adipose tissue inflammation has an impact on liver health and it has been demonstrated that chronic alcohol consumption leads to the expression of pro-inflammatory markers in the adipose tissue. A thorough characterization of alcohol-induced adipose inflammation is lacking, and is important to understand in order to identify immune-related mechanisms that drive this phenomenon. Current therapeutic regimens for alcoholic liver disease are ineffective. It is critical to understand how other organs influence liver injury in this disease when developing novel and effective therapies in the future.
Alcoholic liver disease exhibits a sexual dimorphism; women are more susceptible to liver injury than men and the same paradigm exists in rodent models. Here, I demonstrate that female mice have greater alcohol-induced adipose tissue inflammation than male mice, evidenced by greater expression of pro-inflammatory cytokines and cell markers. Further, female mice also exhibit higher expression of toll-like receptor genes in the adipose tissue, suggesting a potential role for the innate immune system in alcohol-induced adipose inflammation.
Toll-like receptor 4 (TLR4) has been demonstrated to drive inflammation in both the liver and adipose tissue. I used both germline and conditional knockouts of Tlr4 to characterize alcohol-induced changes in the immune cell composition of adipose tissue. Alcohol increased the number of pro-inflammatory adipose tissue macrophages. This macrophage phenotype switching is partially dependent on TLR4; germline, but not myeloid-specific, Tlr4-deletion prevents macrophage phenotype switching. Overall, my work demonstrates that alcohol-induced adipose tissue inflammation is related to liver injury and that TLR4 contributes to adipose macrophage phenotype switching.
4
Fulham, Melissa A. "Characterization of Adipose Tissue Inflammation in Alcoholic Liver Disease." eScholarship@UMMS, 2017. https://escholarship.umassmed.edu/gsbs_diss/940.
Full textAbstract:
Adipose tissue inflammation has an impact on liver health and it has been demonstrated that chronic alcohol consumption leads to the expression of pro-inflammatory markers in the adipose tissue. A thorough characterization of alcohol-induced adipose inflammation is lacking, and is important to understand in order to identify immune-related mechanisms that drive this phenomenon. Current therapeutic regimens for alcoholic liver disease are ineffective. It is critical to understand how other organs influence liver injury in this disease when developing novel and effective therapies in the future.
Alcoholic liver disease exhibits a sexual dimorphism; women are more susceptible to liver injury than men and the same paradigm exists in rodent models. Here, I demonstrate that female mice have greater alcohol-induced adipose tissue inflammation than male mice, evidenced by greater expression of pro-inflammatory cytokines and cell markers. Further, female mice also exhibit higher expression of toll-like receptor genes in the adipose tissue, suggesting a potential role for the innate immune system in alcohol-induced adipose inflammation.
Toll-like receptor 4 (TLR4) has been demonstrated to drive inflammation in both the liver and adipose tissue. I used both germline and conditional knockouts of Tlr4 to characterize alcohol-induced changes in the immune cell composition of adipose tissue. Alcohol increased the number of pro-inflammatory adipose tissue macrophages. This macrophage phenotype switching is partially dependent on TLR4; germline, but not myeloid-specific, Tlr4-deletion prevents macrophage phenotype switching. Overall, my work demonstrates that alcohol-induced adipose tissue inflammation is related to liver injury and that TLR4 contributes to adipose macrophage phenotype switching.
5
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.
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.
6
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.
7
Nath, Bharath D. "Hypoxia Inducible Factors in Alcoholic Liver Disease: A Dissertation." eScholarship@UMMS, 2009. https://escholarship.umassmed.edu/gsbs_diss/525.
Full textAbstract:
Chronic intake of alcohol can result in a range of pathology in the liver. Whilst the earliest changes observed with chronic ethanol, including the accumulation of lipid, or steatosis, are readily reversible upon cessation of alcohol consumption, longer exposure to ethanol may achieve more complex disease states including steatohepatitis, fibrosis, and cirrhosis that can cause irreversible damage and progress to fulminant hepatic failure. A key concept in the pathogenesis of alcoholic liver disease is that chronic ethanol primes the liver to increased injury through an interplay between hepatocytes and non-parenchymal cells, chiefly immune cells, of the liver. These relationships between hepatocytes and non-parenchymal cell types in alcoholic liver disease are reviewed in Chapter 1A.
The Hypoxia Inducible Factors are a set of transcription factors that classically have been described as affecting a homeostatic response to conditions of low oxygen tension. Alcoholic liver disease is marked by increased hepatic metabolic demands, and some evidence exists for increased hepatic tissue hypoxia and upregulation of hypoxia-inducible factor mRNA with chronic alcohol. However, the biological significance of these findings is unknown. In Chapter 1B, we review the literature on recent investigations on the role of hypoxia inducible factors in a broad array of liver diseases, seeking to find common themes of biological function.
In subsequent chapters, we investigate the hypothesis that a member of the hypoxia inducible- factor family, HIF1α, has a role in the pathogenesis of alcoholic liver disease. In Chapter 2, we establish a mouse model of alcoholic liver disease and report data confirming HIF1α activation with chronic ethanol. We demonstrate that HIF1α protein, mRNA, and DNA binding activity is upregulated in ethanol-fed mice versus pair-fed mice, and that some upregulation of HIF2α protein is observable as well. In Chapter 3, we utilize a mouse model of hepatocyte-specific HIF1α activation and demonstrate that such mice have exacerbated liver injury, including greater triglyceride accumulation than control mice. Using cre-lox technology, we introduce a degradation resistant mutant of HIF1α in hepatocytes, and after four weeks of ethanol feeding, we demonstrate that mice with the HIF1α transgene have increased liver-weight to body weight ratio and higher hepatic triglyceride levels. Additionally, several HIF1α target genes are upregulated. In Chapter 4, we examine the relationship between HIF1α activation and hepatic lipid accumulation using a recently published in vitro system, in which lipid accumulation was observed after treating Huh7 cells with the chemokine Monocyte Chemoattractant Protein-1 (MCP-1). We report that MCP-1 treatment induces HIF1α nuclear protein accumulation, that HIF1α overexpression in Huh7 cells induces lipid accumulation, and finally, that HIF1α siRNA prevents MCP-1 induced lipid accumulation. In Chapter 5, we use mouse models to investigate the hypothesis that suppression of HIF1α in hepatocytes or cells of the myeloid lineage may have differing effects on the pathogenesis of alcoholic liver disease. We find that ethanol-fed mice expressing a hepatocyte-specific HIF1α deletion mutant exhibit less elevation in liver-weight body ratio and diminished hepatic triglycerides versus wild-type mice; furthermore, we find that challenging these mice with lipopolysaccharide (LPS) results in less liver enzyme elevation and inflammatory cytokine secretion than in wild-type mice. In Chapter 6, we offer a final summary of our findings and some directions for future work.
8
Choudhury, Mahua Shukla Shivendra D. "Alcohol induced histone acetylation mediated by histone acetyl transferase GCN5 in liver." Diss., Columbia, Mo. : University of Missouri-Columbia, 2008. http://hdl.handle.net/10355/6866.
Full textAbstract:
The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from PDF of title page (University of Missouri--Columbia, viewed on April 6, 2010). Vita. Thesis advisor: Shivendra D. Shukla. "August 2008" Includes bibliographical references
9
Root, Callie. "CTRP3 and Alcoholic Liver Disease in Female Mice." Digital Commons @ East Tennessee State University, 2020. https://dc.etsu.edu/honors/541.
Full textAbstract:
C1q TNF Related Protein 3 (CTRP3), is a cytokine that is primarily secreted from adipose tissue, which classifies it as an adipokine. Our previous research has shown that CTRP3 prevents alcoholic fatty liver disease (ALD) in male mice. However, even when accounting for confounding factors such as absolute and relative alcohol intake, females are more sensitive to the effects of consumption compared to male mice. Therefore, the goal of this project was to determine whether CTRP3 prevented ALD in female mice. Methods: Female wild type (WT) and female CTRP3 transgenic over expressing (Tg) mice were fed an ethanol containing liquid diet (5% v/v) for 6 weeks. Daily weight and food intake measurements were taken and external heat-pads were placed under a portion of the cage to facilitate thermoregulation. Hepatic steatosis was determined by total triglyceride quantification and lipid droplet quantitation in liver sections. Data were analyzed by repeated measures ANOVA, t-test, or Log-rank (Mantel-Cox) test as appropriate. Results: There was no difference between WT and Tg mice in food intake or body weight. There was no difference in survival between WT and Tg mice, however, Tg mice trended towards a reduced rate of survival compared with WT mice (78% in WT versus 44% in Tg, p=0.13). Stereological analysis indicated no difference in the percent of lipid liver volume between the two groups (WT 7.2±3.6 vs Tg 5.1±4.1%). This finding was consistent with no difference in total hepatic triglyceride accumulation observed between WT and Tg mice (12.7±4.4 vs. 13.1±6.8 mg triglycerides/gram liver protein). Conclusion: Combined these data indicate that unlike previous studies with male mice, CTRP3 is not protective against alcohol-induced hepatic steatosis in female mice. Combined, these data indicate that the adipokines such as CTRP3 contribute to physiology in a sex-specific manner.
10
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.
Full textAbstract:
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 foie<br>Non-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
11
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.
Full textAbstract:
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-up<br>Tiivistelmä 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
12
Stewart, Benjamin J. "Characterization of the effects of the lipid peroxidation products 4-hydroxynonenal and 4-oxononenal on hepatic lipid accumulation, VLDL assembly, secretion, and microtubules : relevance to alcoholic liver disease /." Connect to full text via ProQuest. Limited to UCD Anschutz Medical Campus, 2008.
Find full textAbstract:
Thesis (Ph.D. in Toxicology) -- University of Colorado Denver, 2008.<br>Typescript. Includes bibliographical references (leaves 111-122). Free to UCD affiliates. Online version available via ProQuest Digital Dissertations;
13
Iracheta-Vellve, Arvin. "Innate Immunity As Mediator of Cell Death and Inflammation in Alcoholic Liver Disease." eScholarship@UMMS, 2017. https://escholarship.umassmed.edu/gsbs_diss/960.
Full textAbstract:
Central driving forces in the pathogenesis of liver disease are hepatocyte death and immune cell-driven inflammation. The interplay between outcomes, stemming from these two major cell types, is present from the earliest ethanol exposure, and are both determinants in advanced stages of liver disease particularly in alcoholic liver disease (ALD). The complexities associated with advanced ALD are many and therapies are limited. Due to the liver’s role in ethanol metabolism and filtering gut-derived products, it is becoming increasingly clear that innate immunity plays a central role in triggering activation of cell death and inflammatory pathways in ALD. We identified interferon regulatory factor 3 (IRF3) activation as a mediator of hepatocyte death as the first event after ethanol exposure, and the inflammasome as a protein complex responsible for the subsequent inflammatory cascade, driven by the NLRP3 inflammasome.
Our novel findings in murine samples and human patients with alcoholic hepatitis demonstrate that ethanol-induced inflammasome activity results in Caspase-1-mediated pyroptosis and extracellular ASC aggregates in the liver and circulation. Pyroptosis can be abrogated by therapeutic inhibition of inflammasome components, NLRP3 or Caspase-1. Taken together, the event leading to mtDNA release into the cytoplasm is the inception of the pathogenesis of ALD, triggering hepatocyte death, culminating in a pro-inflammatory cascade driven by the NLRP3 inflammasome and pyroptotic release of ASC.
14
Akie, Thomas E. "Regulation of Metabolism by Hepatic OXPHOS: A Dissertation." eScholarship@UMMS, 2010. http://escholarship.umassmed.edu/gsbs_diss/857.
Full textAbstract:
Non-alcoholic fatty liver disease (NAFLD) is an increasingly prevalent issue in the modern world, predisposing patients to serious pathology such as cirrhosis and hepatocellular carcinoma. Mitochondrial dysfunction, and in particular, diminished hepatic oxidative phosphorylation (OXPHOS) capacity, have been observed in NAFLD livers, which may participate in NAFLD pathogenesis.
To examine the role of OXPHOS in NAFLD, we generated a model of enhanced hepatic OXPHOS using mice with liver-specific transgenic expression of LRPPRC, a protein which activates mitochondrial transcription and augments OXPHOS capacity. When challenged with high-fat feeding, mice with enhanced hepatic OXPHOS were protected from the development of liver steatosis and inflammation, critical components in the pathogenesis of NAFLD. This protection corresponded to increased liver and whole-body insulin sensitivity. Moreover, mice with enhanced hepatic OXPHOS have increased availability of oxidized NAD+, which promotes complete fatty acid oxidation in hepatocytes.
Interestingly, mice with enhanced hepatic OXPHOS were also protected from obesogenic effects of long-term high-fat feeding. Consistent with this, enhanced hepatic OXPHOS increased energy expenditure and adipose tissue oxidative gene expression, suggesting a communication between the liver and adipose tissue to promote thermogenesis. Examination of pro-thermogenic molecules revealed altered bile acid composition in livers and serum of LRPPRC transgenic mice. These mice had increased expression of bile acid synthetic enzymes, genes which are induced by NAD+ dependent deacetylase SIRT1 activation of the transcriptional co-regulator PGC-1a. These findings suggest that enhanced hepatic OXPHOS transcriptionally regulates bile acid synthesis and dictates whole-body energy expenditure, culminating in protection from obesity.
15
Akie, Thomas E. "Regulation of Metabolism by Hepatic OXPHOS: A Dissertation." eScholarship@UMMS, 2015. https://escholarship.umassmed.edu/gsbs_diss/857.
Full textAbstract:
Non-alcoholic fatty liver disease (NAFLD) is an increasingly prevalent issue in the modern world, predisposing patients to serious pathology such as cirrhosis and hepatocellular carcinoma. Mitochondrial dysfunction, and in particular, diminished hepatic oxidative phosphorylation (OXPHOS) capacity, have been observed in NAFLD livers, which may participate in NAFLD pathogenesis.
To examine the role of OXPHOS in NAFLD, we generated a model of enhanced hepatic OXPHOS using mice with liver-specific transgenic expression of LRPPRC, a protein which activates mitochondrial transcription and augments OXPHOS capacity. When challenged with high-fat feeding, mice with enhanced hepatic OXPHOS were protected from the development of liver steatosis and inflammation, critical components in the pathogenesis of NAFLD. This protection corresponded to increased liver and whole-body insulin sensitivity. Moreover, mice with enhanced hepatic OXPHOS have increased availability of oxidized NAD+, which promotes complete fatty acid oxidation in hepatocytes.
Interestingly, mice with enhanced hepatic OXPHOS were also protected from obesogenic effects of long-term high-fat feeding. Consistent with this, enhanced hepatic OXPHOS increased energy expenditure and adipose tissue oxidative gene expression, suggesting a communication between the liver and adipose tissue to promote thermogenesis. Examination of pro-thermogenic molecules revealed altered bile acid composition in livers and serum of LRPPRC transgenic mice. These mice had increased expression of bile acid synthetic enzymes, genes which are induced by NAD+ dependent deacetylase SIRT1 activation of the transcriptional co-regulator PGC-1a. These findings suggest that enhanced hepatic OXPHOS transcriptionally regulates bile acid synthesis and dictates whole-body energy expenditure, culminating in protection from obesity.
16
Trepo, Eric. "Role of genetic factors in the progression of fibrosis in alcoholic liver disease and chronic hepatitis C." Doctoral thesis, Universite Libre de Bruxelles, 2012. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/209659.
Full textAbstract:
La maladie alcoolique du foie (MAF) et l’hépatite C chronique (HCC) sont les causes les plus fréquentes de cirrhose, carcinome hépatocellulaire (CHC) et transplantation hépatique dans les pays industrialisés. La fibrose hépatique est le stigmate lésionnel de la progression de la maladie vers la cirrhose comme dans toutes les hépatopathies chroniques. Certains facteurs de risque cliniques environnementaux ont été identifiés. Toutefois, ils n’expliquent pas l’extrême variabilité individuelle de la progression de la fibrose. L’influence ethnique à développer une maladie plus sévère ainsi que les études de concordance des jumeaux mono- et di-zygotiques sur la prévalence de la cirrhose alcoolique ont suggéré l’existence de facteurs génétiques associés. Les nombreuses études de gènes candidats réalisées n’ont identifié que très peu de variants associés de manière reproductible. Pour l’HCC par exemple, le score de risque de cirrhose ou « CRS » a montré sa capacité à prédire une fibrose avancée dans diverses cohortes caucasiennes. Récemment, une étude d’association pangénomique (GWAS) dans la stéatohépatopathie non-alcoolique (NAFLD) a mis en évidence un singleton (single nucleotide polymorphism [SNP]) particulier (rs738409 C>G) dans le gène PNPLA3. Ce dernier s’est révélé être, dans diverses études, le SNP ayant l’impact le plus robuste et le plus reproductible dans cette maladie. Par ailleurs, ce même variant a également été significativement associé à la cirrhose alcoolique chez les hispaniques.<p><p>Les travaux réalisés dans le cadre de cette thèse ont permis de montrer que :<p><p>1) Le CRS avait la capacité de prédire la progression de la fibrose chez des patients caucasiens ayant une HCC dans 2 cohortes européennes indépendantes.<p><p>2) Par ailleurs, dans la MAF, nous avons répliqué chez des patients caucasiens l’association entre le SNP rs738409 dans le gène PNPLA3 et la cirrhose. Nous avons également montré pour la première fois, que l’expression de PNPLA3 était significativement diminuée chez les patients avec une fibrose plus avancée. De plus, nous avons observé dans 2 cohortes européennes que rs738409 était également associé à la prévalence du CHC.<p><p>3) Enfin, nous avons également mis en évidence l’impact de ce même SNP sur la stéatose hépatique et la fibrose dans l’HCC sans toutefois qu’il influence la réponse à la thérapie antivirale dans 3 cohortes caucasiennes indépendantes.<p><p>Ainsi de manière remarquable, un même SNP (rs738409) apparait associé à des lésions hépatiques sévères dans les trois pathologies hépatiques chroniques les plus fréquentes (la MAF, l’HCC et la NAFLD). Ceci suggère des voies pathogéniques communes de la fibrogénèse hépatique. Par ailleurs, ces travaux soulignent indirectement que les GWAS ont la capacité d’ouvrir de nouvelles voies physiopathologiques et d’identifier de nouveaux variants, gènes ou région génétiques capables de constituer de nouveaux biomarqueurs et cibles thérapeutiques dans l’HCC et la MAF.<br>Doctorat en Sciences médicales<br>info:eu-repo/semantics/nonPublished
17
Fisher, Leslie Reginald. "Evaluation of high-throughput methodology for multi-gene screening in patients with Non-Alcoholic Fatty Liver Disease (NAFLD)." Thesis, Stellenbosch : Stellenbosch University, 2011. http://hdl.handle.net/10019.1/17896.
Full textAbstract:
Thesis (MScMedSc)--Stellenbosch University, 2011.<br>ENGLISH ABSTRACT: Non-Alcoholic Fatty Liver Disease (NAFLD) is the most prevalent chronic liver disease in Western countries and is considered the hepatic manifestation of the Metabolic Syndrome (MetS). Its heterogeneous nature ranges from hepatic steatosis through steatohepatitis to advanced fibrosis and cirrhosis where the ingestion of significant amounts of alcohol has been excluded. The disease profile of NAFLD and its necro-inflammatory subset Nonalcoholic Steatohepatitis (NASH) were described in the parent study, which provided a clinically well-characterised patient cohort for the present investigation. South African patients with NASH had significantly higher mean serum cholesterol and triglyceride levels than those with fatty liver only.
The objective of this study was to implement a high-throughput real-time polymerase chain reaction (PCR) method in our laboratory to enable the assessment of cardiovascular genetic risk factors in NAFLD patients. The specific aims were to determine the clinical utility and perform analytical validation of each mutation included in the multi-gene cardiovascular disease (CVD) screening assay. The Pathology Supported Genetic Testing (PSGT) concept developed at our department provides a practical approach to personalized medicine. The CVD multi-gene screen analyses key metabolic pathways relating to atherogenic dyslipidaemia, chronic inflammation, hypercoagulation and iron dysregulation implicated in insulin resistance, which is known to be a universal factor in the pathogenesis of NAFLD. Deleterious low-penetrance mutations in the APOE (APOE2 and E4 alleles), MTHFR (677C>T and 1298A>C), F2 (20210G>A), FV (1691G>A, Leiden) and HFE (C282Y and H63D) genes were included for analysis due to their important role as genetic contributors to these biological processes. A total of 178 patients diagnosed with NAFLD and 75 controls were studied using direct DNA sequencing and a RT-PCR system for mutation detection. In addition, two patients with high ferritin levels were included as case studies. A significant association was found between HFE mutations and elevated Alanine Transaminase (ALT) levels in the NAFLD population (p = 0.04). This discovery is interpreted as the identification of a subset of patients at greater risk of developing progressive liver damage who would benefit most from genetic testing to direct more aggressive therapy at an earlier stage. The necessity of an integrative, systems-based network approach was demonstrated to more accurately distinguish between Hereditary Haemochromatosis (HH) and Insulin Resistance-associated Hepatic Iron Overload (IR-HIO) syndrome in obese patients. The PSGT approach to personalized medicine facilitates diagnosis of CVD subtypes, prevention of cumulative risk and the formulation of gene-based intervention programs tailored to the needs of the patient.
These findings support the clinical utility of the CVD multi-gene test to guide chronic disease risk management in patients with NAFLD. The HFE mutation detection component of this test is of particular relevance in directing an effective treatment strategy in patients with a medical history of CVD and/or high iron stores.<br>AFRIKAANSE OPSOMMING: Nie-Alkoholiese Vettige Lewer Siekte (NAFLD) is die mees algemene kroniese lewer siekte in Westerse lande en word bestempel as die hepatiese manifestasie van die Metaboliese Sindroom (MetS). Die heterogene natuur van NAFLD strek van hepatiese steatose deur steatohepatietis tot gevorderde fibrose en sirrose waar grootskaalse alkohol inname uitgesluit is. Die siekte-profiel van NAFLD en sy nekro-inflammatoriese subtipe Nie-Alkoholiese Steatohepatietis (NASH) is reeds beskryf in die ouer studie, wat ‗n klinies goed-gekarakteriseerde pasiënt groep vir die huidige ondersoek daar gestel het. Suid-Afrikaanse pasiënte met NASH het beduidend hoër gemiddelde serum cholesterol en trigliseried vlakke in vergelyking met slegs vettige lewer.
Die doel van hierdie studie was om ‗n hoë deurvoer rieëltyd polimerase kettingreaksie (RT-PCR) metode in ons laboratorium te implimenteer om kardiovaskulêre genetiese risiko faktore in NAFLD pasiënte te ondersoek. Die spesifieke mikpunte was om die kliniese nut en analitiese geldigheid van elke mutasie wat ingesluit is in die multi-geen kardiovaskulêre siekte (KVS) siftings toets vas te stel. Die Patologie Ondersteunde Genetiese Toetsing (PSGT) konsep wat by ons departement ontwikkel is, verskaf ‗n praktiese benadering tot persoonlike medisyne. Die KVS multi-geen toets analiseer belangrike metaboliese weë verwant aan atherogene dyslipidemie, kroniese inflammasie, oormatige bloedstolling en yster disregulering wat betrokke is by insulien weerstand wat bekend is as ‗n universele factor in the patogenese van NAFLD. Nadelige lae-penetrasie mutasies in die APOE (APOE2 en E4 allele), MTHFR (677C>T en 1298A>C) F2 (20210G>A), FV (1691G>A, Leiden) en HFE (C282Y en H63D) gene was ingesluit vir analise as gevolg van hul belangrike rol as genetiese bydraers tot die bogenoemde biologiese prosesse. ‗n Totaal van 178 pasiënte gediagnoseer met NAFLD en 75 kontroles is bestudeer deur gebruik te maak van direkte DNA volgordebepaling en ‗n RT-PCR metode vir mutasie opsporing. Twee pasiënte met verhoogde ferritien vlakke is ook as gevalle studies ingesluit.
‗n Beduidende assosiasie is gevind tussen HFE mutasies en verhoogde Alanien Transaminase (ALT) vlakke in die NAFLD studiepopulasie (p = 0.04) wat aanduidend is van ‗n subgroup van pasiënte wat die meeste baat sal vind uit genetiese toetsing om meer aggressiewe behandeling te rig op' n vroeër stadium. Die noodsaaklikheid van 'n geïntegreerde, stelsels-gebaseerde netwerk benadering is gewys om meer akkuraat te onderskei tussen Oorerflike Hemochromatose (HH) en Insulien Weerstand-geassosieerde Hepatiese Yster Oorlading (IR-HIO) sindroom in vetsugtige pasiënte. Die PSGT benadering tot persoonlike medisyne formuleer geen-gebaseerde intervensie programme aangepas tot die behoeftes van die pasiënt ek maak diagnose van KVS-subtipes en voorkoming van kumulatiewe risiko moontlik.
Hierdie bevindinge ondersteun die kliniese nut van die KVS multi-geen toets om riglyne vir die risikobestuur van kroniese siektes soos NAFLD daar te stel. Die HFE mutasie opsporings komponent van hierdie toets is van besondere belang om 'n effektiewe strategie vir die behandeling van pasiënte met 'n mediese geskiedenis van KVS en/of hoë yster vlakke daar te stel.
18
Zhao, Ping. "The influence of alcohol on acetaminophen hepatotoxicity : CYP2E1 induction and selective mitochondrial glutathione depletion /." Thesis, Connect to this title online; UW restricted, 2002. http://hdl.handle.net/1773/7952.
Full text
19
Ho, Chi-tat, and 何志達. "A study of the effects of (-)-epigallocatechin-3-gallate (EGCG) on a clinically relevant rat model of non-alcoholic fatty liver diseases(NAFLD)." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2010. http://hub.hku.hk/bib/B45153036.
Full text
20
Rodrigo, Torres Daniel. "Paper de les cèl·lules progenitores hepàtiques en l’hepatitis alcohólica i la regeneració hepàtica." Doctoral thesis, Universitat de Barcelona, 2016. http://hdl.handle.net/10803/399931.
Full textAbstract:
La malaltia hepàtica per consum d'alcohol és una hepatopatia crònica amb alta taxa de mortalitat. Aquests pacients poden presentar episodis d'hepatitis alcohòlica (HA), caracteritzats histològicament per dany hepatocel·lular, colèstasi, esteatosi, fibrosi i infiltrat important de cèl·lules inflamatòries, principalment neutròfils. Actualment, els tractaments existents no són efectius en tots els pacients, sent necessari explorar teràpies alternatives.
El fetge posseeix una capacitat de regeneració única. Després d'un dany hepàtic crònic, la capacitat replicativa dels hepatòcits queda compromesa i dels canals de Hering emergeixen i proliferen les cèl·lules progenitores hepàtiques (CPH). Aquestes cèl·lules, en quiescència en un fetge sa, s'activarien després d'un dany, donant lloc a la reacció ductular (RD), la proliferació de les branques terminals de l'arbre biliar. No obstant, el seu grau de contribució a generar nous hepàtocits in vivo és desconegut. Recentment, mitjançant tècniques de seguiment de llinatge cel·lular s'ha avaluat la participació de les CPH en la regeneració hepàtica, amb resultats contradictoris.
L'objectiu d'aquesta tesi és estudiar la presència i paper de les CPH en l'HA i analitzar el seu grau de contribució a la regeneració hepàtica en situació fisiològica i després d'un dany hepàtic. A part, hem avaluat el perfil d'expressió gènica de les CPH i l'efecte que té aquest perfil en el reclutament de neutròfils. En primer lloc, hem observat com marcadors de CPH (EpCAM, KRT7 i PROM1) estan sobreexpressats en fetges de pacients amb HA comparats amb fetges sans i de pacients amb altres etiologies. A més, PROM1 i KRT7 són bons marcadors prognòstics per a predir la mortalitat a curt termini en pacients amb HA. Finalment, hem confirmat per immunohistoquímica en aquests pacients la presència de CPH i d'una important RD formada per cèl·lules KRT7 i EpCAM positives, així com d'hepatòcits que expressen EpCAM, suggerint els seu origen en les CPH.
La generació de nous hepatòcits per part de les CPH s'ha avaluat mitjançant un ratolí transgènic que permet fer un seguiment de llinatge de cèl·lules de l'epiteli biliar HNF1β positives i la seva progènie. En situació fisiològica, hem observat per immunohistoquímica com la contribució de cèl·lules HNF1β positives a la generació d'hepatòcits és nul·la, al no observar-se hepatòcits expressant el producte del gen reporter β-GAL. En canvi, només en situacions específiques de dany hepàtic crònic (model per dieta CDE) s'observa una població d'hepatòcits doble positius pel marcador d'hepatòcits HNF4α i el gen reporter YFP, demostrant que una població d'hepatòcits té origen en cèl·lules HNF1β positives. No obstant, aquesta contribució és mínima.
Finalment, a partir d'RNA aïllat de cèl·lules HNF1β positives de dos models animals on s'indueixen les CPH (dietes CDE i DDC), s'ha realitzat un microarray que ha permès analitzar el perfil d'expressió gènic de les CPH i determinar gens i vies de senyalització diferencialment expressats entre aquests models. Aquest anàlisi ha determinat que les CPH posseeixen un perfil inflamatori en el model DDC, on no contribueixen a la generació d'hepatòcits al sobreexpressar quimiocines proinflamatòries involucrades en el reclutament de neutròfils, suggerint que les CPH participarien en el seu reclutament durant un dany hepatìc crònic. Aquest perfil inflamatori és també present en cèl·lules de la RD aïllades de pacients amb HA.
En aquesta tesi s'ha conclòs que l'HA es caracteritza per la presència de CPH i d'una important RD. Una major expressió de marcadors de CPH s'associa a major severitat del dany hepàtic i a major mortalitat a curt termini en pacients amb HA. En ratolins, les cèl·lules de l'epiteli biliar no contribueixen a generar nous hepatòcits. Només després d'un dany hepàtic específic, tot i tenir potencial per a generar nous hepatòcits, les CPH contribueixen mínimament, establint els hepatòcits preexistents com a principals responsables de la regeneració hepàtica.<br>Alcoholic liver disease (ALD) is a main cause of chronic liver disease with high mortality. Some ALD patients develop episodes of alcoholic hepatitis (AH), an acute event in a chronic episode of ALD, histologically characterized by the presence of fibrosis, hepatocellular damage and inflammatory response, mainly neutrophils.
After persistent liver damage, hepatocyte proliferation is compromised, and liver progenitor cells (LPC), located in the canals of Hering and in quiescence in healthy liver, are activated and start to proliferate, giving rise to what is known as ductular reaction (DR). However, the extent of LPC contribution to liver recovery and hepatocyte generation after injury remains controversial.
In this doctoral thesis we have increased the current knowledge regarding the role of LPC in liver regeneration using a translational approach. First, we observed that an increased expression of LPC markers (KRT7, PROM1, EpCAM) correlates positively with severity of liver disease and short-term mortality in patients with HA. In addition, we identified by immunohistochemistry in these patients an increase of LPC population and an important DR, as well as EpCAM-positive hepatocytes, suggesting a population of hepatocytes with LPC origin.
Furthermore, using a transgenic HNF1bCreERROSA26RLacZ/YFP mice that allowed us to trace the fate of LPC and their progeny, we shed light on LPC contribution to liver regeneration. In homeostasis and in most liver injury models, LPC are capable to generate biliary cells but do not participate in hepatocyte generation. Only in certain injury conditions (CDE diet) HNF1β cells contribute to newly-generated hepatocytes population, but minimally, supporting the hypothesis that existent hepatocytes are the main source of new hepatocytes.
We also performed a microarray of isolated LPC from two models with remarkable DR and LPC expansion, with (CDE diet) or without (DDC diet) contribution to hepatocytes. Transcriptomic analysis showed differences in LPC gene expression in both models, suggesting that the type of damage determines LPC gene expression profile and their contribution to hepatic regeneration. An inflammatory LPC profile, expressing chemokines involved in neutrophil recruitment, is associated with poor contribution to regeneration. These results suggest that neutrophil recruitment during injury is triggered by LPC chemokine production. This profile resembles to LPC profile obtained after isolating by laser-capture microdissection KRT7-positive DR cells from HA patients. After sequencing their RNA, we also identified in HA new genes and signalling pathways that could play an important role in LPC activation and DR activation.
The data presented in this thesis provide new information regarding LPC presence an DR expansion in HA. Besides, we shed light on the role of LPC and their contribution to liver regeneration in mice. Finally, we identified new genes involved in LPC activation that will help to better understand their role in liver regeneration.
21
Yenilmez, Batuhan O. "DEVELOPMENT OF AN RNAi THERAPEUTIC STRATEGY AGAINST NON-ALCOHOLIC STEATOHEPATITIS (NASH)." eScholarship@UMMS, 2021. https://escholarship.umassmed.edu/gsbs_diss/1158.
Full textAbstract:
Nonalcoholic steatohepatitis (NASH) is a severe liver disorder characterized by triglyceride accumulation, severe inflammation, and fibrosis. With the recent increase in prevalence, NASH is now the leading cause of liver transplantation, with no approved therapeutics available. Despite years of research, the exact molecular mechanism of NASH progression is not well understood, but fat accumulation is believed to be the primary driver of the disease. Therefore, diacylglycerol O-acyltransferase 2 (DGAT2), a key enzyme in triglyceride synthesis, has been explored as a NASH target. RNAi-based therapeutics is revolutionizing the treatment of liver diseases, with recent chemical advances supporting long term gene silencing with single subcutaneous administration. Here we identified a hyper-functional, fully chemically stabilized GalNAc conjugated siRNA targeting DGAT2 (Dgat2-1473) that upon injection elicits up to three months of DGAT2 silencing (>80-90%, p<0.0001) in wild-type and NSG-PiZ “humanized” mice.
Using an obesity-driven mouse model of NASH (ob/ob-GAN), Dgat2-1473 administration prevents and reverses triglyceride accumulation (> 50%, p:0.0008), resulting in significant improvement of the fatty liver phenotype. However, surprisingly, the reduction in liver fat didn’t translate into a similar impact on inflammation and fibrosis. Thus, while Dgat2-1473 is a practical, long-lasting silencing agent for potential therapeutic attenuation of liver steatosis, combinatorial targeting of a second pathway may be necessary for therapeutic efficacy against NASH.
22
Jariwala, Nidhi H. "Characterization of Staphylococcal nuclease and tudor domain containing protein 1 (SND1) as a molecular target in Hepatocellular carcinoma and Non-alcoholic steatohepatitis." VCU Scholars Compass, 2017. https://scholarscompass.vcu.edu/etd/5183.
Full textAbstract:
CHARACTERIZATION OF STAPHYLOCOCCAL NUCLEASE AND TUDOR DOMAIN CONTAINING PROTEIN 1 (SND1) AS A MOLECULAR TARGET IN HEPATOCELLULAR CARCINOMA AND NON-ALCOHOLIC STEATOHEPATITIS
Nidhi Jariwala, PhD
A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Integrative Life Sciences
Virginia Commonwealth University, 2017
Devanand Sarkar, M.B.B.S., PhD.
Associate Professor, Department of Human and Molecular Genetics
Virginia Commonwealth University
Richmond, Virginia
SND1, a subunit of the miRNA regulatory complex RISC, has been implicated as an oncogene in hepatocellular carcinoma (HCC). Oncoprotein SND1 regulates gene expression at a post-transcriptional level in multiple cancers including hepatocellular carcinoma (HCC). In the present study, we characterize oncogenic functions of SND1 in HCC employing a novel transgenic mouse model (Alb/SND1) and present SND1 as a potential molecular target in HCC management. We show that Alb/SND1 mice develop spontaneous HCC with partial penetrance and exhibit more highly aggressive HCC induced by chemical carcinogenesis. Livers from Alb/SND1 mice exhibit a relative increase in inflammatory markers and spheroid-generating tumor initiating cells (TiC). Mechanistic investigations defined roles for Akt and NF-κB signaling pathways in promoting TiC formation in Alb/SND1 mice. Intravenous administration of the selective SND1 inhibitor 3', 5'-deoxythymidine bisphosphate (pdTp) inhibited tumor formation without effects on body weight or liver function. We conclude that SND1 drives pro-oncogenic transcriptomic and proteomic changes in hepatocyte resulting in aggressive HCC. SND1 specific RNA interactome is identified with RNA immunoprecipitation sequencing (RIPSeq) approach. With an adjusted p value of2-fold enrichment over control, 282 mRNAs were identified to significantly associate with SND1 protein. We focused on the tumor suppressor Protein Tyrosine Phosphatase non-receptor type 23 (PTPN23) because its regulation by SND1 and its role in HCC are not known. In current study, we confirm that SND1 post-transcriptionally downregulates PTPN23. Pursuing functional studies with tetracycline inducible overexpression system, we validate that PTPN23 inhibits tyrosine kinase signaling, proliferation, epithelial to mesenchymal transition, migration, invasion and in vivo tumorigenesis.
Alb/SND1 mice also manifest steatosis and fibrosis at one year of age. Coupled with a pro-inflammatory hepatic phenotype, we conclude that Alb/SND1 livers present NASH. High fat diet causes severe NASH and aggressive NASH induced HCC in Alb/SND1 mice. Serum and hepatic lipid profiling shows that hepatocyte specific SND1 overexpression associate with elevated triglyceride and cholesterol LDL levels. Contrarily, hepatocyte specific deletion of SND1 (SND1ΔHEP) in vivo, significantly protects against age dependent steatosis. Association of SND1 in NASH pathology is novel discovery and we present preliminary evidence confirming role of SND1 in promoting NASH.
23
Pretorius, Jakobus. "Investigation of the relationship between genetic and environmental risk factors associated with obesity and insulin resistance in South African patients with non-alcoholic fatty liver disease(NAFLD)." Thesis, Stellenbosch : Stellenbosch University, 2012. http://hdl.handle.net/10019.1/71689.
Full textAbstract:
Thesis (MSCMedSc)--Stellenbosch University, 2012.<br>Includes bibliography<br>ENGLISH ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease in the world. The disease spectrum of NAFLD extends from steatosis (types 1,2) to non-alcoholic steatohepatitis (NASH) with inflammation (types 3,4). The aims of the study were 1) to analytically validate high-throughput real time polymerase chain reaction (RT-PCR) assays for three selected single nucleotide polymorphisms (SNPs), FTO rs9939609 (intron 1 T>A), TNF-α rs1800629 (-308 G>A) and PPARγ rs1801282 (Pro12Ala, 34 C>G), and 2) to perform genotype-phenotype association studies in relation to biochemical abnormalities, disease severity and age of onset.
A total of 119 patients with fatty liver identified on ultrasound, including 88 histologically confirmed NAFLD patients, and 166 control individuals were genotyped for the three selected SNPs. RT-PCR validated against direct sequencing as the gold standard was used for detection of genetic variation. All three SNPs were in Hardy Weinberg equilibrium in the study population, except for a deviation in genotype distribution detected for PPARγ rs1801282 in the NAFLD patient subgroup (p<0.001). After adjustment for age and gender, the risk-associated FTO rs9939609 A-allele was detected at a significantly higher frequency in the Caucasian compared with Coloured patients (p=0.005). The opposite was detected for the risk-associated TNF-α rs1800629 A-allele, which occurred at a significantly higher frequency in the Coloured compared with Caucasian NAFLD patients (p=0.034).
The onset of fatty liver disease symptoms was on average 5 years younger in the presence of each risk-associated TNF-α rs1800629 A-allele (p=0.028). When considered in the context of an inferred genotype risk score ranging from 0-6, disease onset occurred on average 3 years earlier (p=0.008) in the presence of each risk-associated FTO A-allele, TNF-α A-allele or PPARγ C-allele. After adjustment for age, gender and race, no differences in genotype distribution or allele frequencies were observed between histologically confirmed NAFLD (types 1,2) and NASH (types 3,4) patients, while the minor allele frequency for the TNF-α rs1800629 was significantly higher in the total NAFLD (types 1-4) (p=0.047) as well as NASH subgroup (NAFLD types 3,4) (p=0.030) compared with obese patients without a histologically confirmed NAFLD diagnosis. A significant correlation was furthermore observed between the number of TNF-α rs1800629 A-alleles and increasing CRP levels (p=0.029), with a favourable reduced effect in the presence of low- to moderate alcohol intake. The average waist circumference of physically active NAFLD patients was 12% lower than in physically inactive patients (p=0.004).
In view of the results presented in this study, the inclusion of the selected SNPs, and in particular the pro-inflammatory TNF-α rs1800629 polymorphism, may be considered as part of a comprehensive cardiovascular risk evaluation of NAFLD patients. Ultimately, early detection of patients with fatty liver disease symptoms and effective intervention based on the underlying disease mechanism may prevent progression from NAFLD to NASH, shown to be an independent risk factor for cardiovascular diseases.<br>AFRIKAANSE OPSOMMING: Nie-alkoholiese lewervervetting (NALV) is die mees algemene kroniese lewersiekte in die wêreld. Die siektespektrum van NALV strek van steatose (vervette lewer tipes 1,2) tot steatohepatitis met inflammasie (NASH tipes 3,4). Die doel van die studie was 1) om analities die hoë omset polimerase kettingreaksie (RT-PKR) metode te valideer vir die geselekteerde enkel nukleotied polimorfismes (ENPs) FTO rs9939609 (intron 1 T>A), TNF-α rs1800629 (-308 G>A) en PPARγ rs1801282 (Pro12Ala, 34 C>G), en 2) om genotipe-fenotipe assosiasie studies uit te voer ten opsigte van relevante biochemiese abnormaliteite, graad van die siekte en aanvangsouderdom.
’n Totaal van 119 pasiënte met vervette lewers is geïdentifiseer met behulp van ultraklank, insluited 88 histologies-bevestigde NALV pasiënte, en 166 kontrole individue. Hierdie pasiënte is gegenotipeer vir die 3 geselekteerde ENP’s. RT-PKR gevalideer met direkte DNA volgorde bepaling as die goue standaard, is gebruik vir opsporing van genetiese variasie. Al die ENP’s was in Hardy Weinberg ekwilibrium in die studie populasie, behalwe vir ’n afwyking in genotipe verspreiding waargeneem vir PPARγ in die NALV subgroep (p<0.001). Nadat aanpassings gemaak is vir ouderdom en geslag, is die risiko-geassosieerde FTO rs9939609 A-alleel waargeneem teen ’n betekenisvol hoër frekwensie in die Kaukasiese pasiënte in vergelyking met Kleurling pasiënte (p=0.005). Die teenoorgestelde is waargeneem vir die risiko-geassosieerde TNF-α rs1800629 A-alleel wat voorgekom het teen ’n betekenisvol hoër frekwensie in die Kleurling NALV pasiënte, in vergelyking met Kaukasiese NALV pasiënte (p=0.034).
Die aanvang van NALV was gemiddeld 5 jaar vroeër in die teenwoordigheid van elke risiko-geassosieerde TNF-α rs1800629 A-alleel (p=0.028). Met inagneming van ’n genotipe risiko telling tussen 0–6, het aanvang van siekte gemiddeld 3 jaar vroeër voorgekom (p=0.008) in die teenwoordigheid van elke toenemende risiko-geassosieerde FTO A-alleel, TNF-α A-alleel en PPARγ C-alleel. Nadat aanpassings gemaak is vir ouderdom, geslag en ras, is geen verskille waargeneem in genotipe verspreiding of alleel frekwensies tussen histologies bevestigde NALV (tipes 1,2) en NASH (tipes 3,4) pasiënte nie, terwyl die minor alleel telling vir die TNF-α rs1800629 betekenisvol hoër was in die totale NALV (tipes 1–4) (p=0.047) asook die NASH subgroep (NALV tipes 3,4) (p=0.03) in vergelyking met vetsugtige pasiënte sonder ’n histologies bevestigde diagnose. ‘n Statisties beteknisvolle korrelasie is verder waargeneem tussen die aantal TNF-α rs1800629 A-allele en toenemende CRP vlakke (p=0.029), met n gunstige verlaagde effek in die teenwoordigheid van lae alcohol gebruik. Die gemiddelde middellyf-omtrek van fisies aktiewe NALV pasiënte was 12% minder as fisies onaktiewe pasiente (p=0.004).
Na aanleiding van die resultate van hierdie studie behoort insluiting van geselekteerde ENP’s, en in besonder die pro-inflammatoriese TNF-α rs1800629 polimorfisme, as deel van ’n omvattende kardiovaskulere risiko evaluasie oorweeg te word. Aan die einde van die dag mag vroeë identifikasie van NALV pasiente en effektieve intervensie gebasseer op die onderliggende siekte meganisme, vordering tot NASH verhoed wat getoon is om ’n onafhanklike risiko faktor vir kardiovaskulêre siekte te wees.<br>Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Pathology
24
Sampey, Brante P. "Studies of the adduction of hepatocellular proteins by 4-HNE in animals [sic] models of alcoholic liver disease : systematic analysis of hepatocellular Erk 1/2 modulation and dysregulation of the Erk-Elk-AP1 signal transduction pathway /." Connect to full text via ProQuest. IP filtered, 2005.
Find full textAbstract:
Thesis (Ph.D. in Toxicology) -- University of Colorado, 2005.<br>Typescript. Includes bibliographical references (leaves 141-156). Free to UCDHSC affiliates. Online version available via ProQuest Digital Dissertations;
25
Affò, Silvia. "Cytokines and Cytokine-Receptors in the Pathogenesis of Alcoholic Hepatitis." Doctoral thesis, Universitat de Barcelona, 2014. http://hdl.handle.net/10803/145435.
Full textAbstract:
By performing a translational study we identified a specific pattern of genes differentially regulated in patients with severe alcoholic hepatitis (AH). A functional analysis of the gene expression profile showed several pathways deregulated in AH, including cytokines- cytokine receptor interaction. Within cytokine-cytokine receptor interaction pathway, Fn14 has been identified as the only receptor belonging to TNF superfamily to be exclusively up-regulated in patients with AH, and its expression has been shown to be associated with severity of the disease and mortality. We observed that Fn14 is upregulated in experimental models of progenitor cell expansion and co-expressed with Ep-CAM in livers of patients with AH, suggesting that Fn14 may regulate ductular reaction expansion. Moreover, we showed that Fn14 hepatic expression is regulated by ethanol and pro-fibrogenic factors, suggesting that alcohol abuse together with fibrogenic mediators may be directly responsible for the induction of Fn14 expression in ALD.
Furthermore, transcriptome analysis identified CCL20 as the most up-regulated cytokine in the liver of patients with AH. Hepatic expression and serum levels of CCL20 have been found elevated in patients with AH and have been showed to be associated with key clinical features of the disease such as fibrosis, endotoxemia and short-term mortality. These data suggest that besides playing a role in AH pathogenesis, CCL20 may also be considered as a potential non-invasive biomarker. We found that CCL20 hepatic expression is up-regulated in acute, chronic and acute-on chronic experimental model of liver injury induced by carbon tetrachloride (CCl4) and lipopolysaccharide (LPS) and their combination, respectively. Macrophages and hepatic stellate cells have been identified as the main CCL20 producing cell types in experimental models of acute-on-chronic liver injury. Moreover, we have showed that CCL20 exerts pro-fibrogenic and pro-inflammatory and effects on primary human hepatic stellate cells and on macrophages, suggesting that CCL20 may participate in both hepatic fibrosis and inflammation
during liver disease in an autocrine and paracrine manner. Finally, we have found that CCL20 mediates LPS-induced liver injury by promoting hepatocellular apoptosis, expression of pro-inflammatory and pro-fibrogenic mediators and by enhancing macrophages and neutrophils infiltrate recruitment.
In conclusion, during this thesis we performed two studies leading to the identification of new potential targets for therapy in AH. The identification of Fn14 and CCL20 as new potential targets for therapy in AH and their correlations with key hallmarks of the disease such as ethanol consumption, fibrosis, progenitor cells expansion and endotoxemia underline the complexity of this disease and the crosstalk between many mediators that occurs in AH.
The data presented in this thesis suggest that cytokines and cytokine-receptor pathway could represent a new potential target for therapy in ALD; and also provide new important insights and a useful resource for the study of the pathogenesis of this disease.<br>El consumo de alcohol es una de las causas más importantes de mortalidad que pueden prevenirse en nuestro país. La hepatitis alcohólica (HA) se caracteriza por un proceso de inflamación hepática (fundamentalmente por infiltración de células polimorfonucleares), esteatosis masiva hepática, fibrosis pericelular y daño hepatocelular. En la actualidad no existen tratamientos efectivos para el tratamiento de la HA y por esta razón, existe una clara necesidad de identificar nuevas dianas terapéuticas para tratar a estos pacientes en los diferentes estadios de la enfermedad (esteatosis, inflamación y/o fibrogénesis).
El objetivo principal de esta tesis fue investigar nuevas dianas terapéuticas para el tratamiento de la HA. Para alcanzar dicho objetivo, realizamos estudios traslacionales que permitieran identificar marcadores biológicos alterados en muestras humanas procedentes de hígados de pacientes con HA para estudiar la función que tienen en el desarrollo de la enfermedad in vitro e in vivo en modelos animales de diferentes tipos de daño hepático y valorar si podrían considerarse como dianas terapéuticas.
Mediante la performación de nuestros estudios, identificamos a la vía de citoquinas-receptores de citoquinas como una de las vías con el mayor número de genes diferentemente regulados en pacientes con HA con respecto a controles sanos. Estudios en muestras humanas y en modelos animales de daño hepático nos permitieron identificar al receptor de citoquinas Fn14 y a la citoquina CCL20 como importantes mediadores de la HA, correlacionados tanto con aspectos clínicos característicos así como con la gravedad de la enfermedad. La vía de citoquinas y receptores de citoquinas y, de manera específica Fn14 y CCL20 han sido identificados como novedosos mediadores implicados en la patogénesis de la HA y por lo tanto como potenciales dianas terapéuticas. Por lo tanto, gracias a la identificación de un patrón de los genes diferentemente regulados en la HA, nuestros datos proporcionan importantes resultados novedosos para el estudio de la patogénesis de la HA.
26
Carbone, David L. "Effects of the lipid peroxidation product 4-hydroxy-2-nonenal on protein degradation and refolding pathways /." Connect to full text via ProQuest. IP filtered, 2005.
Find full text
27
Silva, Carolina Solon da 1982. "Apoptose induzida por palmitato em células HEPG2 depende da produção de TNF-Alfa." [s.n.], 2012. http://repositorio.unicamp.br/jspui/handle/REPOSIP/309382.
Full textAbstract:
Orientador: Gabriel Forato Anhê<br>Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas<br>Made available in DSpace on 2018-08-21T11:57:04Z (GMT). No. of bitstreams: 1
Silva_CarolinaSolonda_M.pdf: 587503 bytes, checksum: cd74a1063d709369d29c9a998e1cc9a4 (MD5)
Previous issue date: 2012<br>Resumo: A prevalência de esteato hepatite não alcólica (NASH) aumenta de 20% em indivíduos magros para 80% em pacientes obesos com inflamação hepática caracterizada por elevados níveis de TNF-alfa. Um dos eventos que caracteriza a evolução para NASH é a marcante morte de hepatóciotos resultante da ação do excesso de ácidos graxos livres circulantes. O mecanismo pelo qual o palmitato induz a apoptose é dependente, entre outros parâmetros, do aumento dos níveis de espécies reativas de oxigenio (EROS). O objetivo do presente trabalho foi avaliar se a apoptose de hepatócitos induzida pelo palmitato é dependente do aumento da produção de TNF-alfa. Para testar tal hipótese, utilizamos o Infliximabe, um anticorpo monoclonal específico anti-TNF-alfa, como ferramenta farmacológica para reverter as injúrias provocadas pelo palmitato. Foi observado que após 6 horas de tratamento com o palmitato houve um aumento de expressão de mRNA de TNF-alfa levando a um aumento de apoptose 24 horas após à exposição com o ácido graxo. Este fenômeno concordou temporalmente com um aumento na fosforilação das proteínas IkK, IKbeta e JNK, indicativo de ativação da via de sinalização do TNF-alfa. A apoptose induzida pelo palmitato foi revertida pela adição de um inibidor geral de síntese proteica (Ciclohexamida) ou de um anticorpo neutralizante para o TNF-alfa circulante. Além disso, a produção de EROs e a disfunção mitocondrial induzidas pelo palmitato também foram revertidos por estas estratégias farmacológicas. Com base em tais resultados, concluímos que a apoptose, o acúmulo de EROs e da disfunção mitocondrial induzidas pelo palmitato em células HepG2 são dependentes da produção de TNF-alfa<br>Abstract: In the last three decades, the prevalence of overweight and obesity has been continuously increasing. Obesity is a risk factor for developing a series of diseases such as whole-body insulin resistance and type 2 diabetes mellitus. Adipose tissue, originally considered merely energy storage, today is recognized as an endocrine organ able of secreting a variety of cytokines, hormones and other substances with specific biological activities, such as saturated fatty acids. Both long chain saturated fatty acids, like palmitate, and the proinflammatory cytokines, as TNF-alfa, are known to activate signaling pathways that promote apoptosis. The mechanism by which the palmitate induces apoptosis is dependent on cell type, for example, human hepatocellular carcinoma line (HepG2) treated with palmitate led lipotoxicity and to increased levels of reactive oxygen species (ROS). Thus, the objective of this study was to evaluate whether apoptosis in HepG2 cells is dependent on increased production of TNF-alfa induced by treatment with palmitate. To test this hypothesis, we used the Infliximab, a monoclonal antibody anti-TNF-alfa, as a pharmacological tool to reverse injuries caused by palmitate. We observed that palmitate increased the mRNA for TNF-alfa and phosphorylation of IkK, Ikbeta and JNK, all indicative of activation of inflammatory signaling pathways. Apoptosis induced by palmitate was suppressed by simultaneous treatment with cycloheximide or infliximab. Furthermore, the production of ROS and mitochondrial dysfunction induced by palmitate were also suppressed by these two pharmacological strategies. Based on these results, we conclude that apoptosis and related events such as increased ROS production and mitochondrial dysfunction induced by palmitate in HepG2 cells are dependent on autocrine action of TNF--alfa<br>Mestrado<br>Farmacologia<br>Mestra em Farmacologia
28
Latorre, Luque Jèssica. "Relevance of the epigenetic regulation exercised by hepatic microRNAs in the fatty liver arena: from the bedside to the bench." Doctoral thesis, Universitat de Girona, 2020. http://hdl.handle.net/10803/671499.
Full textAbstract:
Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease worldwide, involving a spectrum of disturbances mainly characterized by fatty acid infiltration and fat deposition in the liver parenchyma. Given that alterations in epigenetic mechanisms have been associated with hepatic metabolic disorders, we focused on the relevance of microRNAs (miRNAs) in the pathophysiology of NAFLD. In this thesis, an analysis of hepatic miRNAs comparing patients with and without NAFLD has shown that the disease is associated with an altered miRNA profile, and that the expression of specific miRNAs is related to changes in gene expression and impaired glucose and lipid metabolism. Additionally, altered regulation of miRNAs has been demonstrated through modulation of AMPK in cell and animal models. Finally, specific miRNAs were observed to partially rescued fatty acid overload and modified lipid profiles within hepatocytes, stressing their potential as epigenetic regulators to combat NAFLD<br>La malaltia de fetge gras no alcohòlic (NAFLD) s’ha convertit en la causa principal de les malalties hepàtiques cròniques a nivell mundial, caracteritzada per la infiltració massiva d’àcids grassos al parènquima hepàtic. Tenint en compte que alteracions en els mecanismes epigenètics s’han associat a trastorns metabòlics del fetge, ens centrem en la rellevància dels microRNAs (miRNAs) en la fisiopatologia de NAFLD. En aquesta tesi, un anàlisi de miRNAs hepàtics comparant pacients amb i sense NAFLD ha demostrat que la malaltia està associada amb un perfil de miRNAs alterat, i que l’expressió d’alguns miRNAs està relacionada amb canvis en l’expressió gènica i amb alteracions en el metabolisme glucídic i lipídic. Addicionalment, s’ha demostrat una alteració de la regulació dels miRNAs a través de la modulació de AMPK en models cel·lulars i animals. I finalment, s’han identificat el potencial terapèutic de miRNAs específics per combatre l’acumulació inadequada d’àcids grassos als hepatòcits
29
Lemmers, Arnaud. "Transition de l'immunité innée à l'immunité adaptative au cours des maladies chroniques du foie: implication de l'axe "Pattern recognition" récepteurs - Interleukine-6-Th17." Doctoral thesis, Universite Libre de Bruxelles, 2009. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/210331.
Full textAbstract:
La muqueuse intestinale puis le foie sont en contact récurrent avec la flore microbienne issue du tube digestif. L’activation des récepteurs reconnaissant des motifs moléculaires microbiens (PRR :Pattern Recognition Receptors) constitue l’élément initial de la réponse inflammatoire de l’immunité innée et oriente le type d’activation de l’immunité adaptative. La première étape entraînera l’expression de médiateurs inflammatoire (cytokines (IL-1, IL-6, TNFα), activation de la réponse de phase aiguë) et le recrutement des cellules effectrices de l’immunité innée (neutrophiles, puis monocytes). L’équilibre entre la tolérance microbienne et l’exacerbation inflammatoire afin d’éliminer l’agent microbien et menant à la destruction tissulaire permet d’atteindre la situation d’homéostasie.<p>Si l’inflammation se perpétue, par exemple en cas de défaut de clairance de l’agent microbien ou de trouble de l’intégrité de la barrière muqueuse, l’inflammation peut devenir chronique. L’IL-6 exerce alors un rôle central dans la transition de l’immunité innée à l’immunité adaptative, en modulant différentiellement l’expression de chimiokines et l’apoptose des cellules immunes menant au remplacement de l’infiltrat neutrophilique par un infiltrat lympho-monocytaire. Par ailleurs, ce climat cytokinique particulier est propice au développement de lignées spécifiques de lymphocytes tels que les lymphocytes T CD4+ sécrétant de l’IL-17 (Th17). Ceux-ci, surtout étudiés dans les défenses anti-bactériennes et fungiques, et dans les maladies autoimmunes, ont été incriminés dans les phénomènes de cytotoxicité et de renouvellement inflammatoire par l’induction d’expression de chimiokines.<p><p>Une fois la barrière intestinale franchie, le foie est le premier organe en contact avec la flore microbienne issue de l’intestin. Certains TLRs ont été démontrés impliqués dans la physiopathologie de la stéatohépatite et dans le processus de fibrose. Ce climat constant d’exposition antigénique est associé en cas de maladie chronique du foie à une exacerbation d’expression de médiateurs infammatoires (IL-1, IL-6, TNFα).<p>Nous avons étudié la modulation d’expression des différents TLRs au cours d’un modèle de maladie alcoolique du foie chez la souris. Cette étude démontrait qu’il existait une majoration d’expression des TLR1, 2, 4, 6, 7, 8 et 9 dépendante du stress oxydatif suite à l’exposition chronique du foie à l’alcool ;celle-ci entraînant davantage de lésions hépatiques lors de l’injection des ligands respectifs de ces différents TLRs.<p>Dans ce contexte, nous avons également étudié l’expression des différentes sous-unités du récepteur à l’IL-6 au cours de deux maladies chroniques du foie chez l’homme :les maladies alcooliques du foie et l’hépatite C chronique. Nous avons mis en évidence que les taux plasmatiques d’IL-6 et de la forme soluble de gp130 augmentaient au cours des maladies chroniques du foie, de manière corrélée à la sévérité. Nous avons également démontré l’effet inhibiteur de sgp130 sur la réponse de phase aiguë dépendante du trans-signaling de l’IL-6 in vitro. Ces données suggèrent que sgp130 contribue au déficit de réponse de phase aiguë observé chez les patients atteints de cirrhose. <p><p>Par ailleurs, vu le contexte « cytokinique » chronique des maladies alcooliques du foie (IL-1 et IL-6), nous avons étudié l’activation de la voie de l’interleukine-17 et des Th17 au cours des maladies alcooliques du foie chez l’homme. Nous avons mis en évidence qu’il existait une activation de cellules circulantes sécrétant de l’IL-17 (comprenant des Th17) au cours de la cirrhose alcoolique stable. Par contre, au sein du foie, l’activation de cellules sécrétant de l’IL-17 était davantage augmentée lors de l’hépatite alcoolique. Nous avons également mis en évidence que les cellules stellées (cellules responsables de la fibrose hépatique) stimulées à l’IL-17 recrutaient les neutrophiles suite à l’expression d’IL-8 et de GROα. Cette nouvelle voie inflammatoire démontrée lors d’une maladie du foie chez l’homme met en évidence l’activation de la voie de l’IL-17 au cours des maladies alcooliques du foie et sa contribution potentielle au recrutement hépatique de neutrophiles au cours de l’hépatite alcoolique aiguë. Cette voie sera explorée dans l’avenir en termes de fonctionnalité et de potentielle cible thérapeutique. <p> <p>En conclusion, tout comme le suggère la littérature pour les maladies autoimmunes (maladie de Crohn, arthrite, sclérose en plaque), il semble que les maladies alcooliques du foie partagent avec ces dernières diverses caractéristiques inflammatoires. La flore microbienne intestinale participe à la physiopathologie des lésions hépatiques, de même que l’activation de PRR (TLR). Par ailleurs, un climat inflammatoire chronique (IL-6,…), contre-régulé par certains mécanismes (sgp130), est associé à la présence périphérique et hépatique de lymphocytes Th17. Cette dernière découverte ouvre de nouvelles perspectives dans la compréhension de la physiopathologie des maladies alcooliques du foie, et peut-être de nouvelles cibles thérapeutiques concernant l’hépatite alcoolique aiguë.<p><br>Doctorat en Sciences médicales<br>info:eu-repo/semantics/nonPublished
30
Barros, Layene Peixoto. "O potencial diagnóstico da fetuina-A sérica como biomarcador para distúrbios metabólicos associados à esteatose hepática não-alcoólica." Botucatu, 2019. http://hdl.handle.net/11449/183469.
Full textAbstract:
Orientador: Roberto Carlos Burini<br>Resumo: Fetuina-A é uma glicoproteína multifuncional, sintetizada pelo fígado como proteína de fase aguda. Atua na inibição da cascata da insulina, e estimula a síntese de citocinas pró-inflamatórias. Assim, sugere-se que a fetuina-A esteja envolvida na patogênese da doença gordurosa hepática não-alcoólica (DGHNA), constituindo-se em um dos seus indicadores. O presente estudo tem como objetivo investigar as concentrações de fetuina-A na DGHNA e sua associação com distúrbios metabólicos, bem como, com o risco de fibrose hepática, e doença cardiovascular (DCV), mediante marcadores bioquímicos. Para tanto, foi realizado estudo transversal com mulheres ingressantes em programa para mudança do estilo de vida. Foram avaliadas 148 mulheres com idade entre 35 a 78 anos, as quais foram submetidas às avaliações clínicas, sócio-demográfica, antropométrica, de consumo alimentar e análises bioquímicas. O nível de significância considerado foi p<0,05. Verificou-se DGHNA, pelo Índice de Gordura Hepática (IGH≥60), em 55,4% das mulheres. Fetuina-A sérica correlacionou-se positivamente com Índice de Massa Corporal, circunferência abdominal, IGH e proteína C-reativa ultra-sensível (PCR-us). A proporção de mulheres com resistência insulínica (RI) pelo modelo homeostático de resistência à insulina (HOMA-IR) foi maior dentre os valores maiores (Tercil 3) de fetuina-A, comparativamente, aos menores valores (Tercil 1). Resultado análogo foi encontrado para a PCR-us, mas não para proteína ligadora de lipopol... (Resumo completo, clicar acesso eletrônico abaixo)<br>Abstract: Fetuin-A is a multifunctional glycoprotein, synthesized by the liver as a acute phase protein. It acts in insulin cascade inhibition, and stimulates pro-inflammatory cytokines. It is postulated that fetuin-A is involved in non-alcoholic fatty liver disease (NAFLD) pathogenesis, as one of its indicators. The present study aims to investigate fetuin-A concentration in NAFLD and its association with metabolic disturbers, as well as with hepatic fibrosis risk, and cardiovascular disease (CVD), through biochemical markers. For that, a cross-sectional study was carried out with women entering a lifestyle modification program. We evaluate 148 women, with age that range from 35 to 78 years old that were submitted to clinical, sociodemographic, anthropometric, food consumption and biochemical evaluation. The statistical significance considered was p<0,05. We verified that NAFLD, measured by Fatty Liver Index (FLI ≥60), was found in 55.4% of women. Serum fetuin-A was positively correlated with Body Mass Index, waist circumference, FLI and high-sensitivity C-reactive protein (hs-CRP). The proportion of women with insulin resistance (IR) by insulin resistance homeostatic model assessment (HOMA-IR), was higher among the higher values (Tercil 3) of fetuin-A, compared to the lowest values (Tercil 1). Analog results were found to hs-CRP, but not to lipopolysaccharide-binding protein (LBP), albuminemia and hepatic fibrosis. After adjustments, HOMA-IR and hs-CRP altered, constitute independent... (Complete abstract click electronic access below)<br>Mestre
31
Teare, Julian Paul. "Studies in alcoholic liver disease." Thesis, Imperial College London, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.297283.
Full text
32
Bayard, Max, and Jim Holt. "Non-Alcoholic Fatty Liver Disease." Digital Commons @ East Tennessee State University, 2007. https://dc.etsu.edu/etsu-works/6495.
Full text
33
Järveläinen, Harri. "Inflammatory responses in alcoholic liver disease." Helsinki : University of Helsinki, 2000. http://ethesis.helsinki.fi/julkaisut/ela/perus/vk/jarvelainen/.
Full text
34
Fang, Che. "Cytokines, alcohol metabolizing enzymes and stress-inducible ER proteins in alcoholic liver disease /." Stockholm, 2000. http://diss.kib.ki.se/2000/91-628-4160-2/.
Full text
35
Mann, Alexander Charles. "Serum protein glycosylation in alcoholic liver disease." Thesis, University of Newcastle Upon Tyne, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.323479.
Full text
36
Levene, Adam Phillip. "Steatosis in non alcoholic fatty liver disease." Thesis, Imperial College London, 2012. http://hdl.handle.net/10044/1/9691.
Full textAbstract:
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.
37
Kendrick, Stuart F. W. "Genetic and epigenetic determinants of alcoholic liver disease." Thesis, University of Newcastle Upon Tyne, 2010. http://hdl.handle.net/10443/1065.
Full textAbstract:
Alcoholic liver disease (ALD) is a significant and growing global health problem, responsible for over 10000 deaths per year in the UK alone. Clinical liver failure can result from gradual, chronic depletion of the hepatocyte pool and replacement with fibrous tissue in cirrhosis or from rapid, acute hepatocellular dysfunction secondary to inflammation in acute alcoholic hepatitis (AAH) which carries a mortality of up to 35% on first presentation. Corticosteroid therapy has shown some benefit in AAH but its utility is limited by uncertainty in patient selection and poor clinical response in a proportion of cases. Our current understanding of AAH pathogenesis attributes hepatocellular dysfunction to the action of supra-physiological concentrations of proinflammatory cytokines. Evidence from animal and human studies suggests that the major source of cytokine release is the hepatic macrophage or Kupffer cell responding to an increased concentration of bacterial endotoxin in portal blood following an ethanol-mediated increase in gut permeability. However, this enhanced and sustained inflammatory response is at odds with the normal response in the liver in which endotoxin tolerance allows bacterial components to be cleared from the blood without an inflammatory response. This study set out to investigate factors that determine the enhanced inflammatory response in AAH and its response to therapy. Genetic analysis revealed a single nucleotide polymorphism in a component of the endotoxin response pathway (the Toll-like receptor adapter molecule MAL) associated weakly with advanced disease in both ALD and the related condition non-alcoholic steatohepatitis. Different alleles associated with advanced disease in the two conditions, suggesting divergent importance of signalling pathways in their pathogenesis. Assays in AAH patients demonstrated that their lymphocyte steroid sensitivity was impaired relative to normal controls, correlated with clinical markers of steroid responsiveness, improved in recovery and could be improved by ex vivo supplementation with theophylline, a known recruiter of histone deacetylases. The role of histone modifications in the enhancement of inflammatory responses in ethanol was investigated in a human macrophage cell-line model which revealed increased histone acetylation at pro-inflammatory cytokine gene promoter regions associated with potentiated cytokine responses to endotoxin after culture in ethanol or its metabolite acetate. This effect was abrogated by knockdown of acetyl-coA synthetases, suggesting that increased synthesis of acetyl-coA from acetate is crucial for histone acetylation and consequent increased cytokine production after ethanol exposure. These findings suggest that while genetic predisposition may have some effect on innate immune responses in the pathogenesis of alcoholic liver disease, the more significant contribution is likely to come from gene-environment interactions such as modulation of histone acetylation by products of ethanol metabolism. This epigenetic relationship between metabolism and gene expression in inflammation, mediated by histone deacetylases such as the sirtuin proteins, may be a novel therapeutic target in ALD and potentially also in other inflammatory conditions.
38
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.
Full textAbstract:
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.
39
Liu, Yang-Lin. "Genomic studies in non-alcoholic fatty liver disease." Thesis, University of Newcastle upon Tyne, 2017. http://hdl.handle.net/10443/3822.
Full textAbstract:
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.
40
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.
Full textAbstract:
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.
41
Niemelä, Onni. "Aminoterminal propeptide of type III procollagen and basement related antigens in alcoholic liver disease." Oulu : University of Oulu, 1985. http://catalog.hathitrust.org/api/volumes/oclc/14472875.html.
Full text
42
Hallsworth, Kate. "Physical activity, exercise and non-alcoholic fatty liver disease." Thesis, University of Newcastle upon Tyne, 2012. http://hdl.handle.net/10443/1510.
Full textAbstract:
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.
43
Dinsmore, W. W. "Studies on alcohol and liver disease." Thesis, University of Aberdeen, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.356812.
Full text
44
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.
Full text
45
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.
Full text
46
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.
Full textAbstract:
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.
47
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.
Full textAbstract:
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.<br>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.
48
Kwong, Eric K. "The Role of Sphingosine Kinase 2 in Alcoholic Liver Disease." VCU Scholars Compass, 2019. https://scholarscompass.vcu.edu/etd/5808.
Full textAbstract:
Alcoholic liver disease (ALD) is one of the most common liver diseases worldwide characterized by the accumulation of lipids within the liver, inflammation and the possibility of progressing to cirrhosis and liver failure. More importantly, there are currently no effective treatments for ALD and liver transplantation remains the only therapeutic option for end-stage liver disease. Previous studies have shown that ALD is a result of a combination of endoplasmic reticulum (ER) stress, lipid metabolism dysregulation and inflammation. It has been previously reported that alcohol disrupts gut microbiota homeostasis and causes increased endotoxins that contribute to the pathology of ALD. However, the detailed mechanism(s) underlying ALD and disease progression is poorly understood. We have discovered that sphingosine kinase 2 (SphK2) deficient (SphK2-/-) mice on an alcohol diet exhibit increased steatosis and inflammation compared to wild type mice. Sphingosine 1-phosphate receptor 2 (S1PR2) and SphK2 have been previously shown to play a key role in nutrient metabolism and signaling. However, their roles in alcohol-induced liver injury have not been characterized.
The overall objective of this study is to determine the molecular mechanism(s) by which disruption of S1PR2-mediated SphK2 signaling contributes to ALD. The effects of alcohol on mouse primary hepatocytes and cultured RAW264.7 macrophages were examined. The acute on chronic alcohol mouse model from NIAAA that recapitulates the drinking pattern of human ALD patients was used to study the effects of SphK2 deficiency in ALD. In addition, 60-day chronic alcohol mouse model was used to determine whether a more severe form of ALD was present in SphK2-/- mice. The results indicated that SphK2-/- mice on an alcohol diet exhibited an increased amount of hepatic steatosis compared to wild type mice. Genes regulating lipid metabolism were also dysregulated in SphK2-/- mice. SphK2-/- mice also had increased inflammation and liver injury as shown by an upregulation of inflammatory markers and increased levels of liver enzymes. Moreover, SphK2 protein expression levels were downregulated in the human livers of alcoholic cirrhotic and hepatocellular carcinoma (HCC) patients. These findings contribute to a greater understanding of the pathophysiology of ALD and could provide information on the development of novel therapeutics against ALD.
49
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.
Full textAbstract:
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.
50
Ramsay, Lesley Anne. "Humoral responses to acetaldehyde-modified protein antigens." Thesis, Anglia Ruskin University, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.286770.
Full text