Ursodeoxycholic acid exerts farnesoid X receptor-antagonistic effects on bile acid and lipid metabolism in morbid obesity
Ursodeoxycholic acid exerts farnesoid X receptor-antagonistic effects on bile acid and lipid metabolism in morbid obesity
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DOI：
10.1016/j.jhep.2014.12.034
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发表时间：
2015-06-01
影响因子：
25.7
通讯作者：
Trauner, Michael
中科院分区：
文献类型：
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作者：
Mueller, Michaela;Thorell, Anders;Trauner, Michael
背景和目标：胆汁酸（BA）是肝脏BA和脂质代谢的主要调节剂，但其在非酒精性脂肪性肝病（NAFLD）中的作用机制仍知之甚少。本研究旨在探讨熊去氧胆酸（UDCA）在调节病态肥胖NAFLD患者肝脏和内脏白色脂肪组织（vWAT）之间关于BA和胆固醇代谢以及脂肪酸/脂质分配的相互作用中的分子和生化机制。在这项随机对照药效学研究中，我们分析了血清，40例接受UDCA治疗的匹配良好的病态肥胖患者的肝脏和vWAT样本（20 mg/kg/天）或在减肥手术前三周不治疗。短期UDCA给药通过减少循环成纤维细胞生长因子19和法尼醇X受体（FXR）活化刺激BA合成，导致由升高的C4和7 α-羟基胆固醇反映的胆固醇7 α-羟化酶诱导。增强的BA形成消耗肝脏和LDL胆固醇，随后激活胆固醇合成的关键酶3-羟基-3-甲基戊二酰辅酶A还原酶。减弱的FXR抗脂肪生成作用诱导肝脏中脂肪生成硬脂酰辅酶A去饱和酶（SCD），从而增加肝脏甘油三酯含量。此外，诱导SCD活动在vWAT转移vWAT脂质代谢对产生毒性较小，更多的产脂单不饱和脂肪酸，如oleica.Conclusion：这些数据表明，通过发挥FXR拮抗作用，UDCA治疗NAFLD患者强烈影响胆固醇和BA的合成，并诱导中性脂质蓄积在肝脏和vWAT。(C)2015年欧洲肝脏研究协会。Elsevier B.V.出版，保留所有权利。
Background & Aims: Bile acids (BAs) are major regulators of hepatic BA and lipid metabolism but their mechanisms of action in non-alcoholic fatty liver disease (NAFLD) are still poorly understood. Here we aimed to explore the molecular and biochemical mechanisms of ursodeoxycholic acid (UDCA) in modulating the cross-talk between liver and visceral white adipose tissue (vWAT) regarding BA and cholesterol metabolism and fatty acid/lipid partitioning in morbidly obese NAFLD patients.Methods: In this randomized controlled pharmacodynamic study, we analyzed serum, liver and vWAT samples from 40 well-matched morbidly obese patients receiving UDCA (20 mg/ kg/day) or no treatment three weeks prior to bariatric surgery.Results: Short term UDCA administration stimulated BA synthesis by reducing circulating fibroblast growth factor 19 and farnesoid X receptor (FXR) activation, resulting in cholesterol 7 alpha-hydroxylase induction mirrored by elevated C4 and 7 alpha-hydroxycholesterol. Enhanced BA formation depleted hepatic and LDL-cholesterol with subsequent activation of the key enzyme of cholesterol synthesis 3-hydroxy-3-methylglutaryl-CoA reductase. Blunted FXR anti-lipogenic effects induced lipogenic stearoyl-CoA desaturase (SCD) in the liver, thereby increasing hepatic triglyceride content. In addition, induced SCD activity in vWAT shifted vWAT lipid metabolism towards generation of less toxic and more lipogenic monounsaturated fatty acids such as oleic acid.Conclusion: These data demonstrate that by exerting FXR-antagonistic effects, UDCA treatment in NAFLD patients strongly impacts on cholesterol and BA synthesis and induces neutral lipid accumulation in both liver and vWAT. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.