近日，《肝病学杂志》（Journal of Hepatology）在线发表了中科院上海生科院营养科学研究所应浩研究组有关非酒精性脂肪肝疾病致病机制的最新研究成果。
非酒精性脂肪肝疾病(NAFLD)是一种肝内贮积的甘油三酯含量超过肝脏重量的5%、但无过量饮酒史的临床综合征。其病变主体在肝小叶，以肝细胞脂肪变性和脂肪贮积为病理特征。NAFLD后期会由于血脂紊乱、胰岛素抵抗等引发心脑血管疾病，并引起肝硬化，甚至发展成为肝癌，严重威胁患者健康及生存质量。近年来，NAFLD发病率在我国及世界范围内不断攀升，已经引起了世界各国临床工作者及研究者的广泛关注，但是有关NAFLD发病机制尚不清楚。
应浩研究员指导的博士生宋宜云等发现，配体依赖的转录辅助因子LCOR在非酒精性脂肪肝病人的肝脏中、遗传性肥胖小鼠（ob/ob小鼠）和饮食诱导肥胖的小鼠肝脏中表达下调。研究表明，LCOR可作为甲状腺激素受体（TR）的一种新的转录辅助抑制因子，抑制TR的转录活性，降低TR所调控的脂质生成靶基因的表达。LCOR的这种抑制作用是通过与甾体激素受体辅助激活因子SRC1/3竞争性地结合TR并减少招募到TR靶基因启动子区的SRC1/3来实现的。在肥胖小鼠肝脏中过表达LCOR可以显著降低小鼠肝脏中的甘油三酯的含量，改善肝脏脂肪紊乱状况。
该研究不仅发现了LCOR作为TR转录辅助因子的新的作用机制，还揭示了LCOR在脂质代谢中的重要生理功能，促进了人们对NAFLD的发病机制的认识。更重要的是，该研究还为NAFLD的治疗找到了新的潜在靶标，对治疗NAFLD具有现实的指导意义。
该工作得到了国家自然科学基金委、科技部、中科院“百人计划”、上海市科委的资助。
生物探索推荐英文论文摘要：
Ligand-Dependent Corepressor Acts as a Novel Corepressor of Thyroid Hormone Receptor and Represses Hepatic Lipogenesis in Mice
Abstract
Background & Aims
Transcriptional coregulators assist nuclear receptors to control the transcription and maintain the metabolic homeostasis. Ligand-dependent corepressor (LCOR) was reported to function as a transcriptional corepressor in vitro. We found LCOR expression decreased in the fatty livers of leptin-deficient (ob/ob) mice, diet-induced obese mice, as well as patients, suggesting LCOR may play a role in lipid homeostasis. We sought to investigate the physiological role of LCOR in vivo and elucidate the underlining molecular mechanisms.
Methods
The effect of LCOR on hepatic lipid accumulation and thyroid hormone receptor (TR) mediated expression of lipogenic genes was studied in vitro and in vivo.
Results
Ectopic expression of LCOR via intravenous infection with LCOR adenovirus decreased the hepatic triglyceride level in wild type, ob/ob, and diet-induced obese mice. Interestingly, overexpression of LCOR repressed the thyroid hormone induced expression of lipogenic genes and non-lipogenic genes, and ameliorated hepatic steatosis in obese mice, suggesting that LCOR might regulate lipogenesis as a novel TR corepressor. Furthermore, our study revealed that LCOR could interact with TRβ1 in the presence of ligand, which resulted in competitive binding and reduced recruitment of steroid receptor coactivator-1/3 (SRC-1/3) to the promoter region of TR target genes.
Conclusions
Our data suggest that LCOR is likely to suppress TRβ1-mediated hepatic lipogenesis by decreasing binding and recruitment of SRCs to TRβ1. Our study reveals the physiological function of hepatic LCOR in lipid metabolism and the mechanism by which LCOR regulates lipogenesis. Hepatic LCOR may be a potential target for treating hepatic steatosis.
