Regulation of cholesterol catabolism by bile acids

摘要 过量的胆固醇和胆汁酸与代谢性疾病有关，例如 动脉粥样硬化和胆汁淤积性肝病。该项目的总体目标是了解如何 胆固醇和胆汁酸水平受孤儿核受体、小异二聚体伙伴的调节 (SHP)，它正在成为肝脏代谢途径的关键调节因子。胆固醇转化为 胆汁酸是消除体内胆固醇的主要途径，而胆固醇7a 羟基酶(CYP7A1)在这一过程中起着关键作用。胆汁酸增加抑制转录 CYP7A1通过激活FXR/SHP核受体级联，激活激酶信号转导和 成纤维细胞生长因子15信号通路也可能与SHP有关。我们已经证明了 SHP通过协同募集染色质修饰辅因子到启动子来抑制细胞色素P7A1转录 胆汁酸处理后，导致染色质重塑和基因抑制。然而，小水电和 它的染色质辅助因子被组装并招募到启动子以及多种胆汁酸是否被激活 激酶信号通路通过调节翻译后修饰来影响这些过程 小水电的具体情况仍不清楚。在初步研究中，我们获得了令人振奋的新数据，支持 假设胆汁酸不仅通过FXR诱导SHP的表达，而且还增加了SHP的稳定性和 SHP通过上游抑制蛋白酶体降解和增加SHP总甲基化的活性 磷酸化事件。此外，我们建议SHP的稳定性和活性也受到调节 通过它的配体。为了验证这些假说，我们将：1)定义SHP蛋白酶体降解在 胆汁酸信号。2)研究SHP和甲基化在调节SHP稳定性和活性中的作用。 3)描绘了SHP活性如何受其潜在配体的调节。我们的研究定义了小水电活动如何 胆汁酸及其配体的调节作用将有助于我们理解SHP的作用机制，并可能 揭示治疗代谢和其他疾病的分子靶点，在这些疾病中，SHP起着关键作用。

Abstract Excess amounts of cholesterol and bile acids are associated with metabolic diseases, such as atherosclerosis and cholestatic liver disease. The overall aim of this project is to understand how cholesterol and bile acid levels are regulated by an orphan nuclear receptor, small heterodimer partner (SHP), which is emerging as a critical regulator of hepatic metabolic pathways. Cholesterol conversion to bile acids represents a major route for elimination of cholesterol from the body, and cholesterol 7a hydroxylase (CYP7A1) plays a key role in this process. Increased bile acids repress transcription of CYP7A1 by activating the FXR/SHP nuclear receptor cascade and by activating kinase signaling and fibroblast growth factor 15 signaling pathways which may also involve SHP. We have demonstrated that SHP inhibits CYP7A1 transcription by coordinately recruiting chromatin modifying cofactors to the promoter after bile acid treatment, resulting in chromatin remodeling and gene repression. However, how SHP and its chromatin cofactors are assembled and recruited to the promoter and whether multiple bile acidactivated kinase signaling pathways affect these processes by modulating post-translational modifications of SHP remain unknown. In preliminary studies, we have obtained exciting new data supporting the hypothesis that bile acids not only induce SHP expression via FXR, but also increase the stability and activity of SHP by inhibiting proteasomal degradation and increasing sumoylation of SHP via upstream phosphorylation events. Further, we propose that both the stability and activity of SHP are also regulated by its ligands. To test these hypotheses, we will: 1) Define of the role of proteasomal degradation of SHP in bile acid signaling. 2) Investigate the role of SHP sumoylation in the regulation of SHP stability and activity. 3) Delineate how SHP activity is modulated by its potential ligands. Our studies to define how SHP activity is modulated by bile acids and its ligands will help us understand the mechanism of SHP action and may reveal molecular targets for treating metabolic and other diseases in which SHP plays a key role.