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

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Abstract
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‐β (p‐AMPKβ) 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.