S-Adenosylmethionine attenuates hepatic lipid synthesis in micropigs fed ethanol with a folate-deficient diet
S-Adenosylmethionine attenuates hepatic lipid synthesis in micropigs fed ethanol with a folate-deficient diet
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DOI：
10.1111/j.1530-0277.2007.00407.x
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发表时间：
2007-07-01
影响因子：
3.2
通讯作者：
Halsted, Charles H.
中科院分区：
文献类型：
--
作者：
Esfandiari, Farah;You, Min;Halsted, Charles H.
背景：为了证明蛋氨酸代谢异常在酒精性脂肪变性发病机制中的致病作用，我们测量了在乙醇和叶酸缺乏的饮食中添加s -腺苷蛋氨酸（SAM）对肝脏脂质合成的影响，SAM是一种调节蛋氨酸代谢的代谢物。方法：以尤卡坦微型猪为对照，饲喂叶酸缺乏饲粮，乙醇含量为40% kcal，乙醇中添加0.4 g/ 1000 kcal的SAM，为期14周。在末端大网膜脂肪和肝脏样本中测量组织病理学、甘油三酯水平和转录物以及肝脂合成调节信号的蛋白质水平。结果：在叶酸缺乏的饮食中以40%的卡路里饲喂乙醇14周，增加了肝脏和血浆甘油三酯的控制水平。血清脂联素、肝脏脂联素受体-1转录本（AdipoR1）和磷酸化腺苷单磷酸激酶- β (p-AMPK β)均在乙醇饲粮中降低，并通过添加乙醇饲粮中的SAM维持在正常水平。乙醇喂养激活和添加SAM维持内质酰胺应激诱导的转录因子甾醇调节元件结合蛋白1c （SREBP-1c）及其脂质合成酶乙酰辅酶a羧化酶（ACC）、脂肪酸合成酶（FAS）和甘油-3-磷酸酰基转移酶（GPAT）靶向转录物的控制水平。结论：叶酸缺乏饮食的乙醇喂养通过下调脂联素介导的p-AMPK通路来刺激肝脏脂质合成，从而增加nSREBP-1c及其靶向脂质酶的表达。通过在乙醇饲粮中添加SAM防止肝脏蛋氨酸代谢异常，通过上调脂联素介导的途径减少脂肪酸和甘油三酯的合成，降低肝脏甘油三酯水平。本研究表明，乙醇诱导的肝脏脂质合成在一定程度上是由蛋氨酸代谢异常介导的，并加强了蛋氨酸代谢改变在脂肪变性发病机制中起重要作用的概念。
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-beta (p-AMPK beta) 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.