Artículos de revistas sobre el tema "Ratio total acylcarnitine"

The effects of feeding the peroxisome proliferators ciprofibrate (a hypolipidaemic analogue of clofibrate) or POCA (2-[5-(4-chlorophenyl)pentyl]oxirane-2-carboxylate) (an inhibitor of CPT I) to rats for 5 days on the distribution of carnitine and acylcarnitine esters between liver, plasma and muscle and on hepatic CoA concentrations (free and acylated) and activities of carnitine acetyltransferase and acyl-CoA hydrolases were determined. Ciprofibrate and POCA increased hepatic [total CoA] by 2 and 2.5 times respectively, and [total carnitine] by 4.4 and 1.9 times respectively, but decreased plasma [carnitine] by 36-46%. POCA had no effect on either urinary excretion of acylcarnitine esters or [acylcarnitine] in skeletal muscle. By contrast, ciprofibrate decreased [acylcarnitine] and [total carnitine] in muscle. In liver, ciprofibrate increased the [carnitine]/[CoA] ratio and caused a larger increase in [acylcarnitine] (7-fold) than in [carnitine] (4-fold), thereby increasing the [short-chain acylcarnitine]/[carnitine] ratio. POCA did not affect the [carnitine]/[CoA] and the [short-chain acylcarnitine]/[carnitine] ratios, but it decreased the [long-chain acylcarnitine]/[carnitine] ratio. Ciprofibrate and POCA increased the activities of acyl-CoA hydrolases, and carnitine acetyltransferase activity was increased 28-fold and 6-fold by ciprofibrate and POCA respectively. In cultures of hepatocytes, ciprofibrate caused similar changes in enzyme activity to those observed in vivo, although [carnitine] decreased with time. The results suggest that: (1) the reactions catalysed by the short-chain carnitine acyltransferases, but not by the carnitine palmitoyltransferases, are near equilibrium in liver both before and after modification of metabolism by administration of ciprofibrate or POCA; (2) the increase in hepatic [carnitine] after ciprofibrate or POCA feeding can be explained by redistribution of carnitine between tissues; (3) the activity of carnitine acetyltransferase and [total carnitine] in liver are closely related.

After coronary occlusion and reflow, carbohydrate catabolism is enhanced, whereas fatty acid utilization is delayed. To test the hypothesis that "stunning" of fatty acid use by ischemic heart reflects reduced fatty acid transport into the mitochondria, two activities involved in the transport were examined: carnitine-acylcarnitine translocase and carnitine palmitoyltransferase II (CPT II). The maximal velocity for carnitine exchange of the translocase is reduced 55% in mitochondria isolated from ischemic canine heart (60-min left circumflex occlusion). Mitochondria from ischemic heart show 50% depletion in total matrix glutathione, a 200% increase in glutathione disulfide (GSSG), and an 80% decrease in the ratio of reduced glutathione (GSH) to GSSG, suggesting that the loss of translocase activity may be a consequence of protein sulfhydryl modifications. In support of this, treatment of these mitochondria with the sulfhydryl-reducing agents, GSH or dithiothreitol, restores carnitine exchange to control. Partial return of mitochondrial GSH and a decrease in GSSG are observed with a 20-min reperfusion of the ischemic myocardium. Continued depression in carnitine exchange with reperfusion suggests that other mechanisms may prevent restoration of activity. Import of palmitoylcarnitine on the translocase is coupled to palmitoyl-CoA production by CPT II. Mitochondria from ischemic heart with decreased coupling activity also have the lowest palmitoylcarnitine-supported respiratory rates, suggesting that in severely ischemic tissue the translocation-transesterification sequence may become rate limiting to fatty acid oxidation.

Background: Carnitine deficiency is common in patients on dialysis. Serum free carnitine concentration is significantly lower in patients on hemodialysis (HD) than in healthy individuals. However, there are few reports on serum free carnitine concentration in patients on peritoneal dialysis (PD). Methods: We examined serum concentrations of total, free, and acylcarnitine and the acylcarnitine/free carnitine ratio in 34 PD and 34 age-, sex-, and dialysis duration-matched HD patients. We investigated the prevalence of carnitine deficiency and clinical factors associated with carnitine deficiency in the PD group. Results: Prevalence of carnitine deficiency was 8.8% in the PD group and 17.7% in the HD group (p = 0.283). High risk of carnitine deficiency was found in 73.5% of the PD group and 76.4% of the HD group (p = 0.604). Carnitine insufficiency was found in 82.3% of the PD group and 88.2% of HD group (p = 0.733). Multivariate analysis revealed that duration of dialysis and age were independent predictors of serum free carnitine level in the PD group. Conclusions: The prevalence of carnitine deficiency, high risk of carnitine deficiency, and carnitine insufficiency in PD patients was 8.8%, 73.5%, and 82.3%, respectively. These rates were comparable to those in patients on HD.

This investigation was aimed to study the effect of 2,3-dimercapto-1-propanesulfonic acid (DMPS) on mercuric chloride (HgCl2)-induced alterations in urinary excretion of various carnitine fractions including free carnitine (FC), acylcarnitine (AC), and total carnitine (TC). Different groups of Wistar male rats were treated with HgCl2 at the doses of 0.1, 0.5, 1.0, 2.0, and 3.0 mg/kg body weight, and the animals were sacrificed at 24 hours following HgCl2 injection. A separate batch of animals received HgCl2 (2 mg/kg) with or without DMPS (100 mg/kg) and sacrificed at 24 or 48 hours after dosing. Administration of HgCl2 resulted in statistically significant and dose-dependent increase in the urinary excretion of FC, AC, and TC in rats. However, the ratio of urinary AC:FC was significantly decreased by HgCl2. Pretreatment with DMPS offered statistically significant protection against HgCl2-induced alterations in various urinary carnitine fractions in rats.

Background Metabolic syndrome (MS) is a construct used to separate “healthy” from “unhealthy” obese patients, and is a major risk factor for type 2 diabetes (T2D) and cardiovascular disease. There is controversy over whether obese “metabolically well” persons have a higher morbidity and mortality than lean counterparts, suggesting that MS criteria do not completely describe physiologic risk factors or consequences of obesity. We hypothesized that metabolomic analysis of plasma would distinguish obese individuals with and without MS and T2D along a spectrum of obesity-associated metabolic derangements, supporting metabolomic analysis as a tool for a more detailed assessment of metabolic wellness than currently used MS criteria. Methods Fasting plasma samples from 90 adults were assigned to groups based on BMI and ATP III criteria for MS: (1) lean metabolically well (LMW; n = 24); (2) obese metabolically well (OBMW; n = 26); (3) obese metabolically unwell (OBMUW; n = 20); and (4) obese metabolically unwell with T2D (OBDM; n = 20). Forty-one amino acids/dipeptides, 33 acylcarnitines and 21 ratios were measured. Obesity and T2D effects were analyzed by Wilcoxon rank-sum tests comparing obese nondiabetics vs LMW, and OBDM vs nondiabetics, respectively. Metabolic unwellness was analyzed by Jonckheere-Terpstra trend tests, assuming worsening health from LMW → OBMW → OBMUW. To adjust for multiple comparisons, statistical significance was set at p < 0.005. K-means cluster analysis of aggregated amino acid and acylcarnitine data was also performed. Results Analytes and ratios significantly increasing in obesity, T2D, and with worsening health include: branched-chain amino acids (BCAAs), cystine, alpha-aminoadipic acid, phenylalanine, leucine + lysine, and short-chain acylcarnitines/total carnitines. Tyrosine, alanine and propionylcarnitine increase with obesity and metabolic unwellness. Asparagine and the tryptophan/large neutral amino acid ratio decrease with T2D and metabolic unwellness. Malonylcarnitine decreases in obesity and 3-OHbutyrylcarnitine increases in T2D; neither correlates with unwellness. Cluster analysis did not separate subjects into discreet groups based on metabolic wellness. Discussion Levels of 15 species and metabolite ratios trend significantly with worsening metabolic health; some are newly recognized. BCAAs, aromatic amino acids, lysine, and its metabolite, alpha-aminoadipate, increase with worsening health. The lysine pathway is distinct from BCAA metabolism, indicating that biochemical derangements associated with MS involve pathways besides those affected by BCAAs. Even those considered “obese, metabolically well” had metabolite levels which significantly trended towards those found in obese diabetics. Overall, this analysis yields a more granular view of metabolic wellness than the sole use of cardiometabolic MS parameters. This, in turn, suggests the possible utility of plasma metabolomic analysis for research and public health applications.

CVD is the leading cause of death worldwide, and genetic investigations into the human lipidome may provide insight into CVD risk. The aim of this study was to estimate the heritability of circulating lipid species and their genetic correlation with CVD traits. Targeted lipidomic profiling was performed on 4,492 participants from the Busselton Family Heart Study to quantify the major fatty acids of 596 lipid species from 33 classes. We estimated narrow-sense heritabilities of lipid species/classes and their genetic correlations with eight CVD traits: BMI, HDL-C, LDL-C, triglycerides, total cholesterol, waist-hip ratio, systolic blood pressure, and diastolic blood pressure. We report heritabilities and genetic correlations of new lipid species/subclasses, including acylcarnitine (AC), ubiquinone, sulfatide, and oxidized cholesteryl esters. Over 99% of lipid species were significantly heritable (h2: 0.06–0.50) and all lipid classes were significantly heritable (h2: 0.14–0.50). The monohexosylceramide and AC classes had the highest median heritabilities (h2 = 0.43). The largest genetic correlation was between clinical triglycerides and total diacylglycerol (rg = 0.88). We observed novel positive genetic correlations between clinical triglycerides and phosphatidylglycerol species (rg: 0.64–0.82), and HDL-C and alkenylphosphatidylcholine species (rg: 0.45–0.74). Overall, 51% of the 4,768 lipid species-CVD trait genetic correlations were statistically significant after correction for multiple comparisons. This is the largest lipidomic study to address the heritability of lipids and their genetic correlation with CVD traits. Future work includes identifying putative causal genetic variants for lipid species and CVD using genome-wide SNP and whole-genome sequencing data.

1. The hypothesis that insulin treatment of streptozotocin-diabetic rats does not alter acutely the ability of acylcarnitine synthesis to compete successfully for cytosolic long-chain acyl-CoA [Grantham and Zammit (1988) Biochem. J. 249, 409-414], was tested in vivo by using the technique of selective labelling of hepatic fatty acids in awake unrestrained rats. In the same animals, the partitioning of hepatic fatty acids between acylglycerol and phospholipid synthesis, and of newly labelled triacylglycerol between secretion into the plasma and retention in the liver, was also studied. 2. In untreated diabetic animals, the ratio of fatty acid oxidation to esterification was double that found in normal fed animals, whereas there were no differences in the values of the above-mentioned parameters of glycerolipid metabolism. Thus the insulin status of the rats only has chronic effects on specific aspects of fatty acid metabolism in the liver. 3. Treatment of diabetic rats with insulin resulted in no change in the oxidation/esterification ratio for the first 5 h after the start of insulin administration. Thereafter, there were reciprocal changes in the 14CO2 expired (an index of oxidation) and 14C label recovered in hepatic and plasma glycerolipids. However, the pattern of partitioning observed in normal fed rats was still not re-established after 8 h of insulin treatment. 4. There was a small and transient decrease in the fractional rate of triacylglycerol secretion by the liver at the start of insulin treatment and an increase in the proportion of labelled fatty acid that was utilized for phospholipid synthesis such that phospholipid labelling as a proportion of that of total glycerolipids was doubled after 8 h of insulin treatment. 5. The data are discussed in relation to the roles of insulin in mediating acute changes in hepatic fatty acid metabolism and very-low-density-lipoprotein triacylglycerol secretion by the liver.

Spur cell anemia may occur in severe liver disease including alcoholic cirrhosis. Spur cell anemia red blood cells (RBCs) have a characteristic morphology, with irregular projections, an increased ratio of membrane cholesterol (Ch) to phospholipid, evidence of oxidative damage, and shortened survival resulting in hemolytic anemia. Normal RBCs may acquire many of the features of spur cells either by transfusion into a spur cell patient or in an in vitro model system that loads the RBC membrane with Ch relative to phospholipid by means of Ch-rich, phospholipid-Ch sonicates. We found evidence of abnormal phospholipid repair metabolism in spur cell anemia RBCs characterized by decreased arachidonate (Ar) uptake into phospholipids and by increased uptake into a fatty acid membrane repair intermediate, acylcarnitine (AcylCn). To study the possible modulation of phospholipid repair metabolism in spur cells by Ch-loading, we compared the Ar metabolism of RBCs loaded with Ch in vitro with that of control cells incubated in autologous serum. Ar, a polyunsaturated fatty acid, is especially sensitive to peroxidation and, thus, is likely to be involved in phospholipid repair. Ch-loading decreased the incorporation of [14C]Ar into total lipids (Ch-loaded, 1,113 +/- 48 pmol/10(10) RBCs; control, 1,525 +/- 48 pmol/10(10) RBCs) including phosphatidylethanolamine, phosphatidylserine, and phosphatidylcholine. Uptake of [14C]Ar into AcylCn increased (control AcylCn, 169 +/- 31 pmol/10(10) RBCs; Ch-loaded AcylCn, 196 +/- 35 pmol/10(10) RBCs; P = .0012). Thimerosal, an inhibitor of arachidonoyl- CoA:l-palmitoyl-sn- glycero-3-phosphocholine acyl transferase or lysophosphocholine acyl transferase (LAT), produced a similar pattern of metabolic abnormality, with decreased incorporation into phospholipid but relative increase into AcylCn. We assayed LAT in RBC membranes from Ch-loaded RBCs, using [14C]arachidonoyl CoA as precursor, and found similar decreased LAT activity at concentrations of 1-palmitoyllysophosphatidylcholine (LPC) from 1 to 30 micromol/L. Similar LAT assay results were obtained using [14C]palmitoyl LPC as the precursor. We conclude that Ch-loading of RBC membranes results in inhibition of LAT in the cell-free system in vitro and may account for the inhibited phospholipid repair in Ch-loaded intact RBCs in vitro and in spur cell anemia RBCs in vivo. Decreased ability to replace peroxidized membrane fatty acid by this metabolic pathway may contribute to the hemolytic process in spur cell anemia.

The effects of the ingestion of a meal on the partitioning of hepatic fatty acids between oxidation and esterification were studied in vivo for meal-fed rats. The time course for the reversal of the starved state was extremely rapid and the process was complete within 2 h, in marked contrast with the reversal of the effects of starvation in rats fed ad libitum [A. M. B. Moir and V. A. Zammit (1993) Biochem. J. 289, 49-55]. This rapid reversal occurred in spite of the fact that, in the liver of the meal-fed animals before feeding, a similar degree of partitioning of fatty acids in favour of oxidation was observed as in 24 h-starved rats (previously fed ad libitum). This suggested that the lower degree of ketonaemia observed in meal-fed rats before a meal is not due to the inability of acylcarnitine formation to compete successfully with esterification of fatty acids to the glycerol moiety. Investigation of the possible mechanisms that could contribute towards the rapid switching-off of fatty acid oxidation revealed that this was correlated with a very rapid rise and overshoot in hepatic malonyl-CoA concentration, but not with any change in the activity, or sensitivity to malonyl-CoA, of the mitochondrial overt carnitine palmitoyltransferase (CPT I). The role of these two parameters in the reversal of fasting-induced hepatic fatty acid oxidation was thus the inverse of that observed previously for refed 24 h-starved rats. The rapid increase in [malonyl-CoA] was accompanied by an immediate and complete reversion of the kinetic characteristics (Ka for citrate, expressed/total activity ratio) of acetyl-CoA carboxylase to those found in the post-meal animals, again in contrast with the time course observed in refed 24 h-starved rats [A. M. B. Moir and V. A. Zammit (1990) Biochem. J. 272, 511-517]. The rapidity with which these changes occurred was specific to the partitioning of acyl-CoA; the meal-induced diversion of glycerolipids towards phospholipid synthesis and the acute inhibition of the fractional rate of triacylglycerol secretion occurred with very similar time courses to those observed upon refeeding of 24 h-starved rats. The results confirm the central role played by differences in the dynamics of changes in hepatic malonyl-CoA concentration, and CPT I sensitivity to it, in determining the route through which ingested glucose is converted into hepatic glycogen upon refeeding of starved rats which had previously been meal-fed or fed ad libitum.

Excess fat intake can increase lipid oxidation and expression of mitochondrial proteins, indicating remodeling of the mitochondrial proteome. Yet intermediates of lipid oxidation also accumulate, indicating a relative insufficiency to completely oxidize lipids. We investigated remodeling of the mitochondrial proteome to determine mechanisms of changes in lipid oxidation following high-fat feeding. C57BL/6J mice consumed a high-fat diet (HFD, 60% fat from lard) or a low-fat diet (LFD, 10% fat) for 12 wk. Mice were fasted for 4 h and then anesthetized by pentobarbital sodium overdose for tissue collection. A mitochondrial-enriched fraction was prepared from gastrocnemius muscles and underwent proteomic analysis by high-resolution mass spectrometry. Mitochondrial respiratory efficiency was measured as the ratio of ATP production to O2 consumption. Intramuscular acylcarnitines were measured by liquid chromatography-mass spectrometry. A total of 658 mitochondrial proteins were identified: 40 had higher abundance and 14 had lower abundance in mice consuming the HFD than in mice consuming the LFD. Individual proteins that changed with the HFD were primarily related to β-oxidation; there were fewer changes to the electron transfer system. Gene set enrichment analysis indicated that the HFD increased pathways of lipid metabolism and β-oxidation. Intramuscular concentrations of select acylcarnitines (C18:0) were greater in the HFD mice and reflected dietary lipid composition. Mitochondrial respiratory ATP production-to-O2 consumption ratio for lipids was not different between LFD and HFD mice. After the 60% fat diet, remodeling of the mitochondrial proteome revealed upregulation of proteins regulating lipid oxidation that was not evident for all mitochondrial pathways. The accumulation of lipid metabolites with obesity may occur without intrinsic dysfunction to mitochondrial lipid oxidation.

Chronic hemodialysis (HD) may lead to losses of carnitine from plasma and muscle. Plasma carnitine does not reflect the body content of carnitine. The purpose of this study was the evaluation of total and free plasma and muscle carnitine concentrations (TPC, FPC, TMC, FMC), muscle glycogen and the relationship between plasma and tissue carnitine content and the basic indices of lipid metabolism in HD patients. The studies were conducted in two groups: the first one consisted of 37 HD patients (19 F, 18 M), the second one served as the control and was composed of 29 (10 F, 19 M) patients with healthy kidneys. Tissue specimens in HD patients were taken during surgery on arterio-venous fistula from brachioradial muscle. Carnitine and glycogen measurements were performed using enzymatic methods according to Cederblad and Huijng respectively. Total cholesterol (CH), HDL-CH, and triglycerides were assayed by enzymatic commercial test system (Boehringer-Mannheim, Germany). To summarise, we found the following phenomena in our HD patients in comparison with the controls: 1) In plasma: similar TPC but decreased FPC levels and FPC/TPC ratio which may suggest free carnitine deficiency. 2) In muscle: significantly lower TMC and FMC levels but normal FMC/TMC ratio. 3) Negative correlation between TMC and FMC levels and duration of dialysis treatment. 4) No correlation between plasma and muscle carnitine concentration. 5) Significantly higher concentration of muscle glycogen which could be explained by the changes in the structure of muscle fibres in HD patients and/or lower physical activity. 6) A positive correlation between FPC/APC or FPC/TPC ratio and HDL-CH in HD patients which may suggest that an appropriate proportion between free and acylcarnitines may influence HDL-CH levels in that population. (Int J Artif Organs 2000; 23: 90–6)

Introduction: Altered acylcarnitine concentrations may reflect impaired mitochondrial metabolism and are implicated in cardiovascular disease (CVD). Disturbances in carnitine metabolism have been observed in HIV infection, but it is unknown whether this is related to CVD risk in HIV infected people. Methods: Twenty-six acylcarnitine species were profiled with ultrahigh-performance liquid chromatography/tandem mass spectrometry in 705 men and women with or at risk of HIV infection in the Multicenter AIDS Cohort Study and the Women’s Interagency HIV Study. Using a weighted score approach to define aggregate levels of plasma acylcarnitines, we assessed the associations of short-chain (C2-C7), medium-chain (C8-C14) and long-chain acylcarnitine (C16-C26) with incident carotid plaque, over 7-year follow-up, defined as a carotid artery region with focal intima-media thickness>1.5mm among those with no baseline carotid plaque. Results: The mean age was 45 years and 70% were non-white. The majority (70%) had HIV, and 68% of 394 participants on antiretroviral therapy (ART) had undetectable HIV viral load. Over 7 years, 108 participants developed carotid plaque. Comparing HIV-infected with HIV-uninfected participants, some individual acylcarnitines were higher (C3, C16, C20, C26) while others were lower (C8, C10, C20:4) (all P <0.05), but no significant differences were found in aggregate levels of short-chain, medium-chain, or long-chain acylcarnitines. After adjusted for demographic, behavioral, and HIV infection related factors (HIV serostatus, CD4 cell count and ART), plasma levels of short-chain (risk ratio [RR] = 1.26 [95% CI 1.06-1.50] per standard deviation increment; P=0.008), medium-chain(RR=1.20 [1.01-1.43]; P=0.04) and long-chain acylcarnitines (RR=1.18 [1.00-1.40]; P=0.05) were associated with increased risk of carotid plaque. After further adjusting for traditional CVD risk factors (BMI, total- and HDL-cholesterol, blood pressure, lipid-lowering medication and antihypertensive medication use), the association of short-chain acylcarnitines, but not medium-chain or long-chain acylcarnitines, with carotid plaque remained significant (RR=1.23 [1.04-1.46]; P=0.01). Results were consistent between men and women. Further analyses indicated that the association of short-chain acylcarnitines and carotid plaque was stronger in individuals with HIV infection (RR=1.29 [1.08-1.54]) than those without HIV infection (RR=0.98 [0.66-1.45]), and stronger among HIV+ individuals with detectable viral load (RR =1.42 [1.15-1.75]) than those who had continuous virus suppression (RR =1.02 [0.71-1.47]). Conclusion: Plasma short-chain acylcarnitines were associated with increased risk of carotid plaque formation, independent of traditional CVD risk factors, especially in HIV-infected individuals and those with poor control of HIV viral load.

AbstractAn 8-month-old male infant patient was referred to our institution (from elsewhere) with a history of fever, convulsions, dystonic posturing, altered sensorium, and loss of motor and mental milestones since past 1 month. Upon admission to our institution, a neuroimaging (magnetic resonance imaging of the brain) revealed frontoparietal atrophy, “bat-wing appearance,” and basal ganglia changes. Carnitine and acylcarnitine profile revealed low total carnitine, very low free carnitine, and low free/acylcarnitine ratio, with normal levels of plasma amino acids. Urine gas chromatography mass spectrometry showed an elevated level of ketones (3-hydroxybutyric acid and acetoacetate) and glutaric acid with the presence of 3-hydroxyglutaric acid, suggestive of glutaric aciduria type 1. Diet modification and pharmacotherapy with riboflavin and carnitine arrested the neurological deterioration in the patient.

ObjectiveMedium-chain acyl-CoA dehydrogenase deficiency (MCADD) is a rare inherited metabolic disorder of fatty acid β-oxidation. The present study aimed to evaluate clinical and biochemical manifestations, and the mutation spectrum of this disorder in a large cohort of Chinese patients.MethodsA total of 24 patients were enrolled, and blood acylcarnitine and urinary organic acid levels were measured by tandem mass spectrometry and gas chromatography–mass spectrometry (GC–MS), respectively. Mutations in the ACADM gene were detected by Sanger or next-generation sequencing. Clinical progression, acylcarnitine spectra, and mutations were analyzed and described in detail.ResultsAmong the 24 patients, six cases were diagnosed because of disease onset with symptoms such as vomiting, diarrhea, convulsion, and hypoglycemia; 18 patients without symptoms were diagnosed by newborn screening (NBS). All patients who accepted treatment after diagnosis developed normal intelligence and physique. The concentrations of octanoylcarnitine, the octanoylcarnitine/decanoylcarnitine ratio, and the octanoylcarnitine/acetylcarnitine ratio in the blood and urinary dicarboxylic acid concentrations were consistently elevated. Blood biomarkers failed to decrease after treatment. DNA sequencing revealed seven known and 17 novel mutations in the ACADM gene of patients. Mutation p.T150Rfs∗4 was most frequent, followed by p.R31C, p.F103Y, p.I223T, p.G362E, and c.387+1delG.ConclusionDespite biochemical abnormalities, medium-chain acyl-CoA dehydrogenase deficiency showed relatively mild clinical phenotypes with low mortality and optimistic prognoses in China. NBS is crucial for early diagnosis, treatment, and prognosis.

Introduction: Recently, carnitine has been reported to be useful for improving blood ammonia and cognitive function in cirrhotic patients with subclinical hepatic encephalopathy In Japan, levocarnitine has become available, and there have been several reports in which the carnitine concentration was first measured and whether symptomatic patients improved or not . And, the examination of symptomatic state around the ascites centesis was also carried out. Method: Total carnitine concentration was measured in 5 cirrhotic patients undergoing ascites drainage during our hospital ambulatory, and after ascites drainage, intravenous administration of ercarnitine was conducted to examine whether or not the symptoms improved. Carnitine concentrations were measured before and after dialysis in four non-dialysis patients and one dialysis patient. Oral carnitine was administered in 3 patients (1 dialysis patient) because symptoms of cramps were noted, but in 2 cases. It was administered only after ascites drainage. Case presentation: The case was in a 55 year-old male. The chief complaint was persistent ascites, cramps and general malaise. The patient had a medical history of treatment with radiofrequency ablation (Radiofrequency: RFA) for hepatocellular carcinoma. The patient had been followed up at another hospital for chronic liver cirrhosis type C. Interferon therapy was performed for liver cirrhosis, resulting in a virological complete response (sustained virological response: SVR). The ascites storage was obvious, but the round was repeated from 2 to 3 times a week of golf. Because of frequent leg cramps during and at the end of golf, patients were given branched-chain amino acid preparations and liver protection drugs as oral medications. In a patient with liver cirrhosis, improvement of hepatic encephalopathy associated with decreased carnitine level and decreased ammonia were reported, and deterioration of muscle symptoms associated with carnitine deficiency in a dialysis patient was also reported [1-3]. Therefore, [4] Carnitine concentration and acylcarnitine/free carnitine ratio were measured in this patient, and administration of ercarnitine preparation was started. The carnitine concentration was within the normal range for total carnitine, acylcarnitine, and free carnitine, and the carnitine ratio was not below 0.4, which is the criterion for abnormal values.5). Administration of carnitine preparation was started from 600 mg of ercarnitine. Three days later, the patient’s cramps improved. The appearance of the symptom could not be recognized during and after golf. Carnitine concentration 1 month after administration of carnitine was increased in all cases, and the ratio of acylcarnitine/free carnitine was also decreased (0.388 to 0.253). Carnitine concentration 11 months after administration increased in all cases, and the ratio of acylcarnitine/free carnitine was slightly increased, but was 0.4 or less (Fig 1). The patient is currently hospitalized and discharged from the hospital after drainage of ascites. Ascites drainage was performed once or twice a week. Carnitine administration after ascites drainage increased the carnitine level without cramping or general malaise (Fig 2). Result The total carnitine concentration was within the normal range in the non-dialysis patients, and the concentration of carnitine decreased in the dialysis patients before and after dialysis. Though in 5 cases examined this time, after ascites drainage of 1 case (non-dialysis patient), there was a symptom of the muscle cramp, the appearance of the symptom could not be recognized on the day when this pharmaceutical was administered. Consideration Carnitine is a low-molecular-weight amino acid derivative that Takayanagi argues is important in energy metabolism [6]. For three reasons, one is essential for the transport of long-chain fatty acids into mitochondria. The second regulates the ratio of CoA/acylCoA in mitochondria. Replacement of CoA with carnitine generates free CoA in mitochondria. Third, the acyl compound, which is a cytotoxin, is removed from the cells as a carnitine ester and excreted in urine. Carnitine deficiency is classified as primary or second [7]. Primary carnitine transporter disorders (generalized carnitine deficiency) are congenital carnitine transporter disorders and secondary carnitine disorders are other inborn errors of metabolism or acquired medical conditions 1. Decreased synthesis (Cirrhosis, chronic kidney disease, etc.) 2. Decreased intake (Long-term parenteral nutrition (total potential transition: TPN) management, malnutrition, etc.) 3. Decreased body stores (Pregnant and breastfeeding women, very premature infants, etc.) Medical practices (dialysis, drug-induced). In this case, it is considered that liver cirrhosis is the basis of secondary deficiency, and the carnitine level was within the normal range. However, symptoms of carnitine deficiency are considered to have been present because the administration of ercarnitine improved the symptoms. The development of symptoms of cramps in patients with liver cirrhosis is occasionally observed as one of the adverse reactions. As therapeutic agents, improvement of symptoms may be observed by switching from branched-chain amino acid (branched chain amino acid: BCAA) preparations or BCAA granule preparations to oral nutrition for hepatic failure [8]. It has also been reported that the cause of muscle cramps is peripheral neuropathy, a myogenic mechanism, and a decreased blood concentration of taurine, which suppresses abnormal excitation at the neuromuscular junction. According to Goto et al., administration of BCAA improves the symptoms by decreasing the concentration of free L-tryptophan by increasing the concentration of serum albumin, and by promoting taurine synthesis by correcting the amino acid imbalance. [9]. In this case, oral administration of BCAA granule preparation was possible, but it was difficult to take oral nutrient for liver failure even after ascites drainage due to abdominal distension. Similarly, carnitine deficiency occasionally causes muscle symptoms in dialysis patients [4]. In the 10 study by Sakurauchi et al., 30 maintenance dialysis patients were orally administered 500 mg of L-carnitine over 12 weeks to investigate their physical symptoms. As a result, 2/3 of patients reported improvement in muscle symptoms (Malaise, muscle cramps, muscle aches, etc.). It is said that in dialysis patients with muscle cramps caused by carnitine deficiency, the concentration of carnitine in the blood and muscle decreases, causing a shift from fatty acids to sugars and proteins in the muscle cells (Decreased ATP production due to abnormal fatty acid metabolism and carnitine deficiency in muscle tissue). As a result, sufficient energy production is not achieved in the muscle cells compared to healthy people, and the burden on individual cells increases, resulting in muscle symptoms. With L-carnitine administration, long-chain fatty acids are again fully utilized, and intracellular acyl compounds are washed out and normalized by carnitine, which is considered to be involved in the improvement of muscle symptoms [4,11]. Changes in muscle fibers have also been investigated in dialysis patients and in patients with carnitine deficiency, but there are no characteristic changes [12,13]. However, when carnitine is administered to these patients, an increase in the fiber length of type 1 muscle fibers is observed. These reactions indicate that type 1 muscle fibers are rich in mitochondria and that their metabolism is aerobic. Therefore, carnitine treatment is beneficial in type 1, increases the uptake of fatty acids into mitochondria, increases intracellular metabolism, increases muscle fiber length, and decreases the proportion of atrophied muscle fibers in all muscle fibers. [14]. Although muscle biopsy was not performed in this case, improvement of the symptoms was thought to be achieved by this mechanism. Conclusion The case in which the muscle cramp disappeared in the liver cirrhosis patient with the ercarnitine administration was experienced. The dose and duration of treatment should be considered in future studies. Also, since the serum carnitine fraction is not currently covered by insurance, it is necessary to search for substitute test items in the future.

AbstractThis study investigated how metabolite analysis can explain differences in tissue composition and size in fish from different habitats. We, therefore, studied Nile tilapia (Oreochromis niloticus) from three Ethiopian lakes (Gilgel Gibe, Ziway, and Langano) using dried bloodspot (DBS) analysis of carnitine esters and free amino acids. A total of sixty (N = 60) Nile tilapia samples were collected comprising twenty (n = 20) fish from each lake. The proximate composition of the targeted tissues (muscle, skin, gill, gut, and liver) were analyzed. The DBS samples were analyzed for acylcarnitine and free amino acid profiles using quantitative electrospray tandem mass spectrometry. Metabolite ratios were calculated from relevant biochemical pathways that could identify relative changes in nutrient metabolism. The mean weight of Nile tilapia sampled from each lake showed weight variation among the lakes, fish from Lake Ziway were largest (178 g), followed by Gilgel Gibe reservoir (134 g) and Lake Langano (118 g). Fish from Gilgel Gibe showed significantly higher fat composition in all tissues (P < 0.05) except the liver in which no significant variation was observed. The source of fish affected the tissue fat composition. Marked differences were observed in Nile tilapia metabolic activity between the lakes. For instance, the lower body weight and condition of the fish in Lake Langano coincided with several metabolite ratios pointing to a low flow of glucogenic substrate to the citric acid cycle. The low propionyl to acetylcarnitine ratio (C3:C2) in Gilgel Gibe fish is indicating that more of the available acetyl CoA is not led into the citric acid cycle, but instead will be used for fat synthesis. The metabolic markers for lipogenesis and metabolic rate could explain the high-fat concentration in several parts of the body composition of fish from Gilgel Gibe. Our results show that nutrition-related blood metabolite ratios are useful to understand the underlying metabolic events leading to the habitat-dependent differences in the growth of Nile tilapia, and by extension, other species.

Abstract Obesity is a chronic condition associated with dyslipidemia and insulin resistance. Here, we show that the offspring of obese mothers are dyslipidemic and insulin resistant from the outset. Maternal and cord blood and placental tissues were collected following C-section at term. Patients were grouped as being normal weight (NW, BMI = 18–24.9) or obese (OB, BMI ≥ 30), and separated by fetal sex. We measured plasma lipids, insulin, and glucose in maternal and cord blood. Insulin resistance was quantified using the HOMA-IR. Placental markers of lipid and energy metabolism and relevant metabolites were measured by western blot and metabolomics, respectively. For OB women, total cholesterol was decreased in both maternal and cord blood, while HDL was decreased only in cord blood, independent of sex. In babies born to OB women, cord blood insulin and insulin resistance were increased. Placental protein expression of the energy and lipid metabolism regulators PGC1α, and SIRT3, ERRα, CPT1α, and CPT2 decreased with maternal obesity in a sex-dependent manner (P < 0.05). Metabolomics showed lower levels of acylcarnitines C16:0, C18:2, and C20:4 in OB women’s placentas, suggesting a decrease in β-oxidation. Glutamine, glutamate, alpha-ketoglutarate (αKG), and 2-hydroxyglutarate (2-HG) were increased, and the glutamine-to-glutamate ratio decreased (P < 0.05), in OB placentas, suggesting induction of glutamate into αKG conversion to maintain a normal metabolic flux. Newly-born offspring of obese mothers begin their lives dyslipidemic and insulin resistant. If not inherited genetically, such major metabolic perturbations might be explained by abnormal placental metabolism with potential long-term adverse consequences for the offspring’s health and wellbeing.

Background: Aging is a complex process that results from metabolic activities such as those that generate reactive oxygen species. Metabolomic profiling, an emerging technology, may shed light on metabolites associated with aging and identify key changes associated with premature aging. Methods: A total of 370 metabolites were profiled using liquid chromatography tandem mass spectroscopy (LC-MS) in plasma from 1153 healthy, control subjects in the Women’s Health Initiative. Metabolite levels were log-transformed and standardized, and each considered individually in statistical models. Linear regression models were created with the metabolite as the outcome and age as the primary exposure: <60 (referent), 60-<65, 65-<70, 70-<75, and 75 years and older. Models were adjusted for matching factors in the primary study (race, time period, hysterectomy status, and then additionally for body mass index, medications (antihypertensives, anti-diabetic drugs, aspirin and statins), and creatinine. The likelihood ratio test was used to compare models with age to model without age, with adjustment for false discovery rate (FDR). Significant results were defined as FDR adjusted p<0.05. Results: The median age of the women was 68 years (interquartile range 62-72). After multivariate adjustment, thirty-nine metabolites were significantly associated with age >75, including 12 acylcarnitines, 11 free fatty acids, 9 fatty acid derivatives, 2 amino acids, and 5 additional metabolites. Of these, octadecenoyl-L-carnitine (C18:1) had the strongest age association, with levels 0.70 SD (95% CI: 0.48-0.92) higher on average among women > 75 years compared to women <60 years of age (referent). C22:0 sphingomyelin (SM), threonine and C24:0 SM were negatively associate with age; levels of these metabolites were on average 0.41 to 0.44 SD lower among the women 75 years and older when compared to the youngest women (linear trend FDR-p value <0.05 for all of these metabolites). Conclusions: Multiple metabolites involved in mitochondrial fatty acid oxidation, as well as several associated with insulin resistance, have a strong relationship with age, even after adjusting for multiple age-associated factors.