Regulation of cholesterol catabolism by bile acids

描述（由申请人提供）：该项目的总体目标是了解胆汁酸作为最近发现的控制综合代谢和能量平衡的关键信号分子的作用，以及这一调节途径在肥胖和相关疾病中的功能障碍。肥胖在世界范围内是一种日益严重的流行病。肥胖人群的脂肪肝（脂肪变性）会增加患糖尿病、心脏病甚至肝癌的风险。胰岛素在代谢调节中的作用已被广泛研究，但对BA信号如何整合控制肝脏代谢知之甚少。小异二聚体伴侣（SHP）被认为是BA信号通路的关键参与者。作为对胆囊酸信号传导的响应，SHP通过协调募集组蛋白修饰蛋白（组蛋白甲基化酶和去乙酰化酶）到启动子，介导了限速胆囊酸生物合成基因Cyp7a1的表观遗传抑制。此外，SHP本身的翻译后修饰（PTMs）调节其在肝脏中的水平和活性。然而，这些先前的研究并没有解决

DESCRIPTION (provided by applicant): The overall goal of this project is to understand the role of bile acids as recently recognized key signaling molecules that control integrative metabolism and energy balance and the dysfunction of this regulatory pathway in obesity and related diseases. Obesity is a growing epidemic worldwide. Fatty liver (steatosis) that develops in obese people increases the risk for diabetes, heart disease, and even, liver cancer. The role of insulin in the regulation of metabolism has been extensively studied, but little is known about how BA signaling is integrated to control hepatic metabolism. Small Heterodimer Partner (SHP) has been implicated as a key player in BA signaling pathways. In response to bile acid signaling, SHP mediates the epigenetic repression of Cyp7a1, the rate-limiting bile acid biosynthetic gene, by coordinately recruiting histone-modifying proteins (histone methylases and deacetylases) to the promoter. Further, post-translational modifications (PTMs) of SHP itself regulates its level and activity in the liver. These previous studies, however, did not address the key questions of how the PTM of SHP and the epigenetic histone modifications are regulated in response to BA signaling and how this regulation is altered in pathology, such as fatty liver disease. Answering these questions is the specific goal of the current proposal. Surprisingly, preliminary studies have revealed a role for protein kinase C-zeta (PKC?) in regulating SHP activity in response to bile acid signaling by phosphorylating Thr-55 of SHP which is critical for SHP-repression activity and is a key event upstream of other known PTMs of SHP that control its stability and activity. Notably, PKC? is a negative regulator of obesity-induced inflammation and hepatic steatosis, thus, phosphorylation of SHP by PKC? may be critically involved in bile acid-regulated hepatic metabolism. Based on these studies, we hypothesize that SHP functions as a key epigenetic coordinator in bile acid-regulated hepatic metabolism and that bile acid signaling-induced PTMs of SHP, particularly phosphorylation by PKC?, are critical to its hepatic functions, but, in obesity, PTMs of SHP and SHP-mediated epigenetic regulation are dysregulated, contributing to abnormal hepatic metabolism. To test this hypothesis, we will utilize in vitro and in vivo studies using transgenic and obese mouse models, cultured hepatic cells, and human liver hepatocyes or tissue from normal or fatty liver disease patients. Our specific aims are to: 1) define the role of PTMs of SHP induced by BA signaling (BA or FGF19) in normal hepatic metabolism, focusing on phosphorylation by PKC?? 2) determine whether SHP functions as a key epigenetic coordinator of bile acid responsive hepatic genes, including analyzing global genomic binding sites of SHP and bile acid-mediated epigenetic gene regulation, and 3) investigate whether PTMs of SHP, global SHP binding sites, and SHP-mediated epigenetic events are altered in fatty livers, contributing to metabolic abnormalities in obesity. These studies will elucidate how SHP epigenetically controls BA-regulated hepatic functions, and identify novel potential diagnostic and/or therapeutic targets for metabolic diseases.