Yetti Husna, Naito Hisao, Yuan Yuan, Jia Xiaofang, Hayashi Yumi, Tamada Hazuki, Kitamori Kazuya, Ikeda Katsumi, Yamori Yukio, Nakajima Tamie
Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Department of Public Health, Fujita Health University School of Medicine, Toyoake, Japan.
PLoS One. 2018 Feb 13;13(2):e0192863. doi: 10.1371/journal.pone.0192863. eCollection 2018.
During middle age, women are less susceptible to nonalcoholic steatohepatitis (NASH) than men. Thus, we investigated the underlying molecular mechanisms behind these sexual differences using an established rat model of NASH. Mature female and male stroke-prone spontaneously hypertensive 5/Dmcr rats were fed control or high-fat-cholesterol (HFC) diets for 2, 8, and 14 weeks. Although HFC-induced hepatic fibrosis was markedly less severe in females than in males, only minor gender differences were observed in expression levels of cytochrome P450 enzymes (CYP)7A1, CYP8B1 CYP27A1, and CYP7B1, and multidrug resistance-associated protein 3, and bile salt export pump, which are involved in fibrosis-related bile acid (BA) kinetics. However, the BA detoxification-related enzymes UDP-glucuronosyltransferase (UGT) and sulfotransferase (SULT) 2A1, and the nuclear receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR), were strongly suppressed in HFC-fed males, and were only slightly changed in HFC-diet fed females. Expression levels of the farnesoid X receptor and its small heterodimer partner were similarly regulated in a gender-dependent fashion following HFC feeding. Hence, the pronounced female resistance to HFC-induced liver damage likely reflects sustained expression of the nuclear receptors CAR and PXR and the BA detoxification enzymes UGT and SULT.
在中年时期，女性比男性更不易患非酒精性脂肪性肝炎（NASH）。因此，我们使用已建立的NASH大鼠模型研究了这些性别差异背后的潜在分子机制。将成熟的雌性和雄性易中风自发性高血压5/Dmcr大鼠分别喂食对照饮食或高脂胆固醇（HFC）饮食2周、8周和14周。尽管HFC诱导的肝纤维化在雌性大鼠中明显不如雄性大鼠严重，但在参与纤维化相关胆汁酸（BA）动力学的细胞色素P450酶（CYP）7A1、CYP8B1、CYP27A1和CYP7B1以及多药耐药相关蛋白3和胆汁盐输出泵的表达水平上，仅观察到微小的性别差异。然而，与BA解毒相关的酶尿苷二磷酸葡萄糖醛酸基转移酶（UGT）和磺基转移酶（SULT）2A1，以及核受体组成型雄甾烷受体（CAR）和孕烷X受体（PXR），在喂食HFC的雄性大鼠中受到强烈抑制，而在喂食HFC饮食的雌性大鼠中仅略有变化。在喂食HFC后，法尼酯X受体及其小异二聚体伴侣的表达水平也以性别依赖的方式受到类似调节。因此，雌性对HFC诱导的肝损伤具有明显抗性，这可能反映了核受体CAR和PXR以及BA解毒酶UGT和SULT的持续表达。
