mTOR信号通路在多囊卵巢综合征并发非酒精性脂肪肝发生中的作用

Non-alcholic fatty liver disease (NAFLD) is a common complication of Polycystic Ovary Syndrome (PCOS). Hyperandrogenism and dyslipidemia are the risk factors of PCOS complicated by NAFLD. The mammalian target of rapamycin (mTOR), an intracellular nutrient sensor, is a key regulator in lipid homeostasis and organismal energy metabolism. Our preliminary data showed that high androgen level and high fat diet (HFD) play an important role in inducing PCOS mice complicated by NAFLD. Thus the aim of this project is to study the role for mTOR signaling pathway in the pathogenesis of this syndrome complicated by NAFLD and to reveal the underlying mechanisms. In the first part of the project, we will use androgen in combination with HFD to induce PCOS mouse model complicated by NAFLD. The expression of mTOR and its upstream and downstream molecules will be measured in the liver. By activating or inactivating mTOR, we will show how altered mTOR levels influence the incidence of NAFLD in the PCOS mice. In the second part of the project, the effect of androgen on hepatic lipid metabolism will be investigated at different mTOR expression levels in hepatic cells. The accomplishment of this project will help to illustrate the role for mTOR signaling pathway in the pathogenesis of PCOS complicated by NAFLD and provide the possible therapeutic target and experimental evidence for the intervention and treatment of NAFLD in women with PCOS at early stages.

非酒精性脂肪肝（NAFLD）是多囊卵巢综合征（PCOS）患者常见的并发症，高雄激素血症和脂代谢紊乱是导致PCOS并发NAFLD的危险因素。mTOR是细胞内营养感受分子，在脂质稳态和机体总能量水平的调节中起重要作用。我们的前期结果表明高雄激素水平和高脂饮食（HFD）是诱导PCOS小鼠并发NAFLD的重要因素。本课题旨在研究mTOR信号通路在PCOS并发NAFLD中的作用及其机制。研究内容一将通过雄激素加HFD诱导产生PCOS并发NAFLD小鼠，检测mTOR信号通路在小鼠肝脏中的表达，并通过激活或抑制mTOR，阐明mTOR水平改变对PCOS并发NAFLD发生的影响；研究内容二将在细胞水平研究mTOR表达改变时雄激素对肝脏脂代谢的影响。本课题的开展将有助于阐明mTOR信号通路在PCOS并发NAFLD中的作用，从而为PCOS患者早期干预和治疗NAFLD提供可能的药物靶点和实验依据。

在本课题的资助下，我们共发表了4篇研究论文，2篇中文核心期刊。其中一篇研究论文发表在Biology of Reproduction，在这部分工作中我们发现DHEA或DHEA+60%HFD诱导的PCOS小鼠有类抑郁行为，该行为与脑中单胺神经递质或其代谢产物的减少有关，而高脂饮食则不影响该症状。该论文被英国医学与生物学论文评价和检索系统Faculty of 1000收录，并推荐为优秀论文（very good）。我们在另一篇研究论文中报道：DHEA诱导的PCOS小鼠骨骼肌胰岛素抵抗，该现象与骨骼肌细胞线粒体受损和胰岛素刺激下葡萄糖的摄取减少有关。此外，我们发现DHEA诱导的PCOS小鼠的肝脏中，p-mTOR/mTOR的比值显著低于对照组，细胞实验结果证明雄激素可以改变肝细胞中mTOR的表达。我们的结果提示mTOR及其通路可能参与PCOS的非酒精性脂肪肝的发病机制中。