Department of Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, Essen, Germany.
Hepatology. 2013 Apr;57(4):1394-406. doi: 10.1002/hep.26225.
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.
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.
非酒精性脂肪性肝病（NAFLD）是工业化国家最常见的肝脏疾病，可能发展为脂肪性肝炎（NASH）。细胞凋亡和游离脂肪酸（FFA）诱导的脂毒性是非酒精性脂肪性肝炎发病机制的重要特征。我们已经证明了脂联素在丙型肝炎病毒（HCV）患者脂肪变性肝脏中的肝保护作用，最近的数据将胆汁酸（BA）代谢与 NAFLD 的发病机制联系起来。本研究的目的是确定 BA 和 FFA 代谢之间在 NAFLD 中的潜在相互作用。对 113 名接受减肥手术的病态肥胖患者、健康个体和中度肥胖的 NAFLD 患者的肝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。NAFLD 活动评分（NAS）与 BA 水平呈正相关，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 Na + /牛磺胆酸钠共转运蛋白（NTCP）和 BA 合成酶胆固醇 7α-羟化酶（CYP7A1）在肥胖患者和暴露于 FFA 的肝癌细胞中显著上调。NTCP 和 CYP7A1 的上调表明，随着 BA 浓度的增加，FXR 刺激时未能激活小异二聚体伴侣（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，并在体内和体外均影响 Cyp7A1 的表达。
BA 合成和血清 BA 水平与 NAFLD 疾病严重程度相关，而脂联素呈负相关。FFA 暴露可防止 SHP 介导的 NTCP 和 Cyp7A1 表达抑制，导致 BA 合成和摄取增加。在 NASH 中，BA 积累诱导肝细胞死亡，晚期 FXR 激活由于脂联素水平降低而未能预防肝细胞损伤。早期使用 FXR 配体和/或脂联素受体激动剂可能预防 NASH。
