Okushin Kazuya, Tsutsumi Takeya, Enooku Kenichiro, Fujinaga Hidetaka, Kado Akira, Shibahara Junji, Fukayama Masashi, Moriya Kyoji, Yotsuyanagi Hiroshi, Koike Kazuhiko
Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
Department of Infectious Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
J Gastroenterol. 2016 Aug;51(8):808-18. doi: 10.1007/s00535-015-1148-y. Epub 2015 Nov 25.
Nonalcoholic fatty liver disease (NAFLD) presents as a spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). The latter is progressive, and its pathogenesis remains poorly understood. Recently, bile acid (BA) metabolism has become a therapeutic focus in NASH patients. The aim of the present study was to explore changes in bile acid metabolism in NAFLD patients in the context of disease progression.
We prospectively enrolled patients with clinically suspected NAFLD. Patients taking ursodeoxycholic acid were excluded. The intrahepatic expression levels of genes associated with BA metabolism were determined by quantitative PCR and immunohistochemistry.
Seventy-eight patients (male:female = 49:29) histologically diagnosed with NAFLD were analyzed. The expression levels of farnesoid X receptor, liver receptor homolog 1, and small heterodimer partner, key proteins in BA synthesis, significantly decreased as the NAFLD activity score (NAS) increased in either males or females. The levels of cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme of BA synthesis, were not changed. Notably, the expression levels of a main export transporter, bile salt export pump (BSEP), significantly decreased as the NAS and the each NAS component increased in both genders. The decreases of BSEP levels were also observed by immunohistochemistry, particularly in areas with pronounced fatty changes in cases with high NAS.
The expression levels of the BA export transporter BSEP were inversely correlated with NAS in NAFLD patients. Such down-regulation may cause excessive BA levels in hepatocytes, leading to cell injury. Our findings may afford new insights into the pathogenesis of NASH.
非酒精性脂肪性肝病（NAFLD）表现为从单纯性脂肪变性到非酒精性脂肪性肝炎（NASH）的一系列病变。后者具有进展性，其发病机制仍知之甚少。最近，胆汁酸（BA）代谢已成为NASH患者的治疗焦点。本研究的目的是在疾病进展的背景下探索NAFLD患者胆汁酸代谢的变化。
我们前瞻性纳入临床疑似NAFLD的患者。排除服用熊去氧胆酸的患者。通过定量PCR和免疫组织化学测定与BA代谢相关基因的肝内表达水平。
对78例经组织学诊断为NAFLD的患者（男∶女 = 49∶29）进行了分析。在男性和女性中，随着NAFLD活动评分（NAS）增加，BA合成中的关键蛋白法尼醇X受体、肝脏受体同源物1和小异二聚体伴侣的表达水平均显著降低。BA合成的限速酶胆固醇7α-羟化酶的水平未发生变化。值得注意的是，随着NAS及各NAS组分增加，主要输出转运体胆盐输出泵（BSEP）的表达水平在两性中均显著降低。免疫组织化学也观察到BSEP水平降低，尤其是在NAS高的病例中脂肪变性明显的区域。
NAFLD患者中BA输出转运体BSEP的表达水平与NAS呈负相关。这种下调可能导致肝细胞内BA水平过高，从而导致细胞损伤。我们的研究结果可能为NASH的发病机制提供新的见解。
