Free fatty acids repress small heterodimer partner (SHP) activation and adiponectin counteracts bile acid-induced liver injury in superobese patients with nonalcoholic steatohepatitis
Free fatty acids repress small heterodimer partner (SHP) activation and adiponectin counteracts bile acid-induced liver injury in superobese patients with nonalcoholic steatohepatitis
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DOI：
10.1002/hep.26225
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发表时间：
2013-04-01
期刊：
影响因子：
13.5
通讯作者：
Canbay, Ali
中科院分区：
文献类型：
--
作者：
Bechmann, Lars P.;Kocabayoglu, Peri;Canbay, Ali
非酒精性脂肪性肝病（NAFLD）是工业化国家中最常见的肝脏疾病，并且可能进展为脂肪性肝炎（NASH）。细胞凋亡和游离脂肪酸（FFA）诱导的脂毒性是NASH发病机制的重要特征。我们已经表明脂联素在丙型肝炎病毒（HCV）患者的脂肪变性肝脏中具有保肝作用，并且近期数据将胆汁酸（BA）代谢与NAFLD的发病机制联系起来。本研究的目的是确定NAFLD中BA和FFA代谢之间的潜在相互作用。对113例接受减肥手术的病态肥胖患者、健康个体以及中度肥胖的NAFLD患者的肝脏活检和血清样本进行了研究。与单纯性脂肪变性相比，NASH患者的血清FFA、BA和M30升高，而脂联素显著降低。非酒精性脂肪性肝病活动度评分（NAS）与BA水平相关，与脂联素呈负相关。脂联素与CD95/Fas信使RNA（mRNA）和肝细胞凋亡呈负相关。BA转运体高亲和力钠/牛磺胆酸共转运体（NTCP）和BA合成酶胆固醇7α - 羟化酶（CYP7A1）在肥胖患者以及暴露于FFA的肝癌细胞中显著上调。NTCP和CYP7A1的上调表明，随着BA浓度增加，法尼醇X受体（FXR）受到刺激时无法激活小分子异二聚体伴侣（SHP）。与NAS评分一致，脂联素水平与BA水平呈负相关。脂联素与NTCP相关，并在体内和体外影响Cyp7A1的表达。结论：BA合成和血清BA水平与NAFLD的疾病严重程度相关，而脂联素呈负相关。FFA暴露阻止了SHP介导的对NTCP和Cyp7A1表达的抑制，从而导致BA合成和摄取增加。在NASH中，BA积聚诱导肝细胞死亡，并且由于脂联素水平降低，晚期FXR激活无法预防肝细胞损伤。早期使用FXR配体和/或脂联素受体激动剂治疗可能预防NASH。（《肝脏病学》2013年；57卷：1394 - 1406页）
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in industrialized countries and may proceed to steatohepatitis (NASH). Apoptosis and free fatty acid (FFA)-induced lipotoxicity are important features of NASH pathogenesis. We have shown a hepatoprotective effect of adiponectin in steatotic livers of hepatitis C virus (HCV) patients and recent data links bile acid (BA) metabolism to the pathogenesis of NAFLD. The aim of this study was to identify potential interactions between BA and FFA metabolism in NAFLD. Liver biopsies and serum samples from 113 morbidly obese patients receiving bariatric surgery, healthy individuals, and moderately obese NAFLD patients were studied. Serum FFA, BA, and M30 were increased in NASH versus simple steatosis, while adiponectin was significantly decreased. The NAFLD activity score (NAS) score correlated with BA levels and reversely with adiponectin. Adiponectin reversely correlated with CD95/Fas messenger RNA (mRNA) and hepatocellular apoptosis. The BA transporter high-affinity Na+/taurocholate cotransporter (NTCP) and the BA synthesizing enzyme cholesterol 7 alpha-hydroxylase (CYP7A1) were significantly up-regulated in obese patients and hepatoma cells exposed to FFA. Up-regulation of NTCP and CYP7A1 indicate failure to activate small heterodimer partner (SHP) upon farnesoid X receptor (FXR) stimulation by increasing BA concentrations. In line with the NAS score, adiponectin levels were reversely correlated with BA levels. Adiponectin correlated with NTCP and affects Cyp7A1 expression both in vivo and in vitro. Conclusion: BA synthesis and serum BA levels correlated with disease severity in NAFLD, while adiponectin is reversely correlated. FFA exposure prevented SHP-mediated repression of NTCP and Cyp7A1 expression, which lead to increased BA synthesis and uptake. In NASH, BA accumulation induced hepatocyte cell death and late FXR activation failed to prevent hepatocyte injury due to decreased adiponectin levels. Early treatment with FXR ligands and/or adiponectin-receptor agonists might prevent NASH. (HEPATOLOGY 2013;57:13941406)