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Methionine Metabolism (methionine + metabolism)

Distribution by Scientific Domains

Medical Sciences	100%

Selected Abstracts

Dysregulated Cytokine Metabolism, Altered Hepatic Methionine Metabolism and Proteasome Dysfunction in Alcoholic Liver Disease

ALCOHOLISM, Issue 2005
Craig McClain
Abstract: Alcoholic liver disease (ALD) remains an important complication and cause of morbidity and mortality from alcohol abuse. Major developments in our understanding of the mechanisms of ALD over the past decade are now being translated into new forms of therapy for this disease process which currently has no FDA approved treatment. Cytokines are low molecular weight mediators of cellular communication, and the pro-inflammatory cytokine tumor necrosis factor (TNF) has been shown to play a pivotal role in the development of experimental ALD. Similarly, TNF levels are elevated in the serum of alcoholic hepatitis patients. Abnormal methionine metabolism is well documented in patients with ALD, with patients having elevated serum methionine levels, but low S-adenosylmethionine levels in the liver. On the other hand, S-adenosylhomocysteine and homocysteine levels are elevated in ALD. Recent studies have documented potential interactions between homocysteine and S-adenosylhomocysteine with TNF in the development of ALD. Altered proteasome function also is now well documented in ALD, and decreased proteasome function can cause hepatocyte apoptosis. Recently it has been shown that decreased proteasome function can also act synergistically to enhance TNF hepatotoxicity. Hepatocytes dying of proteasome dysfunction release pro-inflammatory cytokines such as Interleukin-8 to cause sustained inflammation. This article reviews the interactions of cytokines, altered methionine metabolism, and proteasome dysfunction in the development of ALD. [source]

Increased tumor necrosis factor ,,converting enzyme activity induces insulin resistance and hepatosteatosis in mice,

HEPATOLOGY, Issue 1 2010
Loredana Fiorentino
Tumor necrosis factor ,,converting enzyme (TACE, also known as ADAM17) was recently involved in the pathogenesis of insulin resistance. We observed that TACE activity was significantly higher in livers of mice fed a high-fat diet (HFD) for 1 month, and this activity was increased in liver > white adipose tissue > muscle after 5 months compared with chow control. In mouse hepatocytes, C2C12 myocytes, and 3T3F442A adipocytes, TACE activity was triggered by palmitic acid, lipolysaccharide, high glucose, and high insulin. TACE overexpression significantly impaired insulin-dependent phosphorylation of AKT, GSK3, and FoxO1 in mouse hepatocytes. To test the role of TACE activation in vivo, we used tissue inhibitor of metalloproteinase 3 (Timp3) null mice, because Timp3 is the specific inhibitor of TACE and Timp3,/, mice have higher TACE activity compared with wild-type (WT) mice. Timp3,/, mice fed a HFD for 5 months are glucose-intolerant and insulin-resistant; they showed macrovesicular steatosis and ballooning degeneration compared with WT mice, which presented only microvesicular steatosis. Shotgun proteomics analysis revealed that Timp3,/, liver showed a significant differential expression of 38 proteins, including lower levels of adenosine kinase, methionine adenosysltransferase I/III, and glycine N -methyltransferase and higher levels of liver fatty acid-binding protein 1. These changes in protein levels were also observed in hepatocytes infected with adenovirus encoding TACE. All these proteins play a role in fatty acid uptake, triglyceride synthesis, and methionine metabolism, providing a molecular explanation for the increased hepatosteatosis observed in Timp3,/, compared with WT mice. Conclusion: We have identified novel mechanisms, governed by the TACE,Timp3 interaction, involved in the determination of insulin resistance and liver steatosis during overfeeding in mice. (HEPATOLOGY 2009.) [source]

S-adenosylhomocysteine sensitizes to TNF-, hepatotoxicity in mice and liver cells: A possible etiological factor in alcoholic liver disease

HEPATOLOGY, Issue 4 2004
Zhenyuan Song
In alcoholic liver disease, tumor necrosis factor-, (TNF,) is a critical effector molecule, and abnormal methionine metabolism is a fundamental acquired metabolic abnormality. Although hepatocytes are resistant to TNF,-induced killing under normal circumstances, previous studies have shown that primary hepatocytes from rats chronically fed alcohol have increased TNF, cytotoxicity. Therefore, there must be mechanisms by which chronic alcohol exposure "sensitizes" to TNF, hepatotoxicity. S-adenosylhomocysteine (SAH) is product of methionine in transsulfuration pathway and a potent competitive inhibitor of most methyltransferases. In this study, we investigated the effects of increased SAH levels on TNF, hepatotoxicity. Our results demonstrated that chronic alcohol consumption in mice not only decreased hepatic S-adenosylmethionine levels but also increased hepatic SAH levels, which resulted in a significantly decreased S-adenosylmethionine-to-SAH ratio. This was associated with significant increases in hepatic TNF, levels, caspase-8 activity, and cell death. In vitro studies demonstrated that SAH-enhancing agents sensitized hepatocytes to TNF, killing, and the death was associated with increased caspase-8 activity, which was blocked by a caspase-8 inhibitor. In addition, increased intracellular SAH levels had no effect on nuclear factor ,B activity induced by TNF,. In conclusion, these results provide a new link between abnormal methionine metabolism and abnormal TNF, metabolism in alcoholic liver disease. Increased SAH is a potent and clinically relevant sensitizer to TNF, hepatotoxicity. These data further support improving the S-adenosylmethionine-to-SAH ratio and removal of intracellular SAH as potential therapeutic options in alcoholic liver disease. Supplementary material for this article can be found on the HEPATOLOGYwebsite (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html). (HEPATOLOGY 2004;40:989,997.) [source]

S -Adenosylmethionine Attenuates Hepatic Lipid Synthesis in Micropigs Fed Ethanol With a Folate-Deficient Diet

ALCOHOLISM, Issue 7 2007
Farah Esfandiari
Background: To demonstrate a causative role of abnormal methionine metabolism in the pathogenesis of alcoholic steatosis, we measured the effects on hepatic lipid synthesis of supplementing ethanol and folate-deficient diets with S -adenosylmethionine (SAM), a metabolite that regulates methionine metabolism. Methods: Yucatan micropigs were fed folate-deficient diets as control, with ethanol at 40% of kcal, and with ethanol supplemented with SAM at 0.4 g/1,000 kcal for 14 weeks. Histopathology, triglyceride levels and transcripts, and protein levels of the regulatory signals of hepatic lipid synthesis were measured in terminal omental adipose and liver samples. Results: Feeding ethanol at 40% of kcal with folate-deficient diets for 14 weeks increased and supplemental SAM maintained control levels of liver and plasma triglyceride. Serum adiponectin, liver transcripts of adiponectin receptor-1 (AdipoR1), and phosphorylated adenosine monophosphate kinase- , (p-AMPK,) were each reduced by ethanol feeding and were sustained at normal levels by SAM supplementation of the ethanol diets. Ethanol feeding activated and SAM supplementation maintained control levels of ER stress-induced transcription factor sterol regulatory element-binding protein-1c (SREBP-1c) and its targeted transcripts of lipid synthesizing enzymes acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), and glycerol-3-phosphate acyltransferase (GPAT). Conclusions: Ethanol feeding with a folate-deficient diet stimulates hepatic lipid synthesis by down-regulating adiponectin-mediated pathways of p-AMPK to increase the expression of nSREBP-1c and its targeted lipogenic enzymes. Preventing abnormal hepatic methionine metabolism by supplementing ethanol diets with SAM reduces liver triglyceride levels by up-regulation of adiponectin-mediated pathways to decrease fatty acid and triglyceride synthesis. This study demonstrates that ethanol-induced hepatic lipid synthesis is mediated in part by abnormal methionine metabolism, and strengthens the concept that altered methionine metabolism plays an integral role in the pathogenesis of steatosis. [source]

Dysregulated Cytokine Metabolism, Altered Hepatic Methionine Metabolism and Proteasome Dysfunction in Alcoholic Liver Disease

Open-label pilot study of folic acid in patients with nonalcoholic steatohepatitis

LIVER INTERNATIONAL, Issue 2 2007
Phunchai Charatcharoenwitthaya
Abstract: Background/Aims: Folate deficiency disturbs hepatic methionine metabolism and promotes the development of steatohepatitis in animal models. Our aims were (1) to determine the safety and efficacy of folic acid treatment in patients with nonalcoholic steatohepatitis (NASH) on changes in liver biochemistries, and (2) to investigate the presence of subclinical folate deficiency in this population. Methods: Patients with biopsy-proven NASH were treated with folic acid 1 mg/day for 6 months. Liver enzymes and adverse events were monitored every 3 months until completion. Results: Ten patients (one male and nine females) with a median age of 54 years were enrolled in this study. At baseline, the median steatosis grade was 2 (range 1,3), the median necroinflammatory grade was 1 (1,3), and the median fibrosis stage was 2 (0,4). The median level of red cell folate was 526 ng/ml (range 99,708); the normal level was 268,616 ng/ml. One compensated cirrhotic patient had folate deficiency. No serious adverse events occurred. After 6 months of therapy, no significant reductions in serum aspartate and alanine aminotransferase levels (60±25 vs. 54±29, P=0.5 and 86±29 vs. 83±42, P=0.6, respectively), were observed. Serum levels of bilirubin, alkaline phosphatase, albumin, and prothrombin time remained in the normal range during treatment in all patients. Conclusion: Six months of therapy with folic acid at a dose of 1 mg/day, although safe and well tolerated, does not lead to a significant biochemical improvement in patients with NASH. In a small number of patients, folate deficiency was present in only a cirrhotic patient. [source]

Atrophic gastritis as a cause of hyperhomocysteinaemia

ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2004
L. Santarelli
Summary Background :,Hyperhomocysteinaemia is an independent risk factor for atherosclerosis. It is often related to low levels of vitamin B12 and/or folate, enzymatic co-factors of methionine metabolism. Atrophic gastritis, often caused by Helicobacter pylori infection, may impair vitamin absorption. Aim :,To assess whether the presence of atrophic gastritis is associated with hyperhomocysteinaemia via deficiency of its vitamin co-factors. Methods :,Thirty-one patients with atrophic gastritis were recruited. The control group consisted of 28 patients with non-atrophic gastritis, matched with patients for sex, age and body mass index. The presence and degree of gastric atrophy were assessed by histology. H. pylori infection was assessed by histology/serology. Blood samples were collected for the measurement of homocysteine, vitamin B12 and folates. Results :,Multiple logistic regression analysis showed that atrophic gastritis (odds ratio, 5.3; 95% confidence interval, 1.23,25.26; ,2 = 5.2; P = 0.01) and low vitamin B12 (odds ratio, 3.7; 95% confidence interval, 1.03,22.08; ,2 = 3.6; P < 0.05) were both predictors of hyperhomocysteinaemia. None of the other variables considered in the analysis, including H. pylori status, showed a significant association with hyperhomocysteinaemia. Conclusions :,The present study suggests that atrophic gastritis, rather than H. pylori infection per se, may be a contributing factor to hyperhomocysteinaemia, possibly via vitamin B12 malabsorption. [source]

Pre-operative vitamin B infusion and prevention of nitrous oxide-induced homocysteine increase

ANAESTHESIA, Issue 7 2010
L. K. Rao
Summary Nitrous oxide inactivates vitamin B12 with detrimental consequences for folate and methionine metabolism, detectable by an increase in total plasma homocysteine. We hypothesised that a pre-operative vitamin B12 and folate infusion prevents nitrous oxide-induced homocysteine increase. Sixty-three healthy patients having elective surgery were randomly allocated to receive either B-vitamin plus nitrous oxide; placebo plus nitrous oxide or placebo plus air. Fifty-nine patients completed the study. After intravenous B-vitamin infusion, plasma vitamin B12 and folate concentrations increased 35-fold and 12-fold, respectively, on the first postoperative measurement. Patients who received B-vitamins developed a similar increase (18%) in homocysteine after nitrous oxide (1.9 ,mol.l,1; 95% CI 0.2,3.6 ,mol.l,1) as those who did not (22%; 2.7 ,mol.l,1; 95% CI 0.6,4.8 ,mol.l,1). Patients not receiving nitrous oxide had no homocysteine change (0.5 ,mol.l,1; 95% CI ,0.8,1.9 ,mol.l,1), indicating that pre-operative intravenous B-vitamins may not prevent nitrous oxide-induced hyperhomocysteinaemia. [source]