Regulation of cholesterol catabolism by bile acids

描述(申请人提供)：过量的胆固醇和胆汁酸与代谢性疾病有关，如动脉粥样硬化和胆汁淤积性肝病。这个项目的总体目标是了解胆固醇和胆汁酸水平是如何受到一个孤立的核受体和转录抑制因子--小异二聚体伙伴(SHP)的调节的，SHP正在成为一种关键的代谢调节因子。胆固醇转化为胆汁酸是胆固醇从体内清除的主要途径，而胆固醇71羟基酶(CyP7A1)在这一过程中起着关键作用。胆汁酸反馈通过激活多个信号通路抑制CYP7A1的转录，包括胆汁酸受体FXR、细胞激酶信号和FGF15/19肠道-肝脏信号通路诱导的SHP，SHP被认为是所有这些抑制通路中关键的下游调节因子。在初步研究中，我们获得了支持这一假设的数据，即胆汁酸不仅诱导SHP的表达，而且通过抑制蛋白酶体的降解和通过上游磷酸化事件增加SHP的总和基化来增加SHP的稳定性和活性。此外，我们认为SHP的稳定性和活性也受潜在的激动剂3-Cl-AHPC的调节。为了验证这些假说，我们将：1)确定SHP泛素化-蛋白酶体降解在胆汁酸信号转导中的作用。2)研究SHP总和甲基化在SHP抑制活性中的作用。3)阐明3-氯-AHPC对肝细胞SHP活性和稳定性的调节作用。由于SHP在正常生理和疾病过程中起着关键作用，我们的研究旨在确定SHP的肝脏活性是如何被胆汁酸FGF15/19及其配体调节的，这可能为治疗代谢紊乱提供新的分子靶点。公共卫生相关性：过量的胆固醇和胆汁酸与代谢性疾病有关，如动脉粥样硬化和胆汁淤积性肝病。胆汁酸导致肝细胞中小分子异二聚体(SHP)的数量增加，从而抑制胆固醇分解为胆汁酸。该项目的总体目标是了解SHP如何调节胆固醇和胆汁酸水平。已知胆汁酸促进SHP的合成，但SHP的稳定性和活性是否也受到胆汁酸的影响尚不清楚。这些研究将考察胆汁酸和胆汁酸诱导的肠道成纤维细胞生长因子-19和潜在的SHP配体3-Cl-AHPC是否以及如何影响SHP在肝细胞中的稳定性和活性。这些研究将帮助我们了解SHP活性是如何调节的，并可能为治疗代谢性疾病提供新的方法。

DESCRIPTION (provided by applicant): 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 and transcriptional repressor, small heterodimer partner (SHP), which is emerging as a critical metabolic regulator. Cholesterol conversion to bile acids represents a major route for elimination of cholesterol from the body, and cholesterol 71 hydroxylase (CYP7A1) plays a key role in this process. Bile acids feedback-inhibit transcription of CYP7A1 by activating multiple signaling pathways, including SHP induction by the bile acid receptor FXR, cell kinase signaling, and FGF15/19 gut-liver signaling pathway and SHP has been implicated as a key downstream regulator in all these inhibitory pathways. In preliminary studies, we have obtained data supporting the hypothesis that bile acids not only induce SHP expression, 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 the stability and activity of SHP are also regulated by a potential agonist, 3-Cl-AHPC. To test these hypotheses, we will: 1) Define of the role of ubiquitination-proteasomal degradation of SHP in bile acid signaling. 2) Investigate the role of SHP sumoylation in SHP repression activity. 3) Delineate how the activity and stability of SHP are regulated by 3-Cl-AHPC in hepatic cells. Since SHP plays a critical role in normal physiology and also in disease processes, our studies to define how the hepatic activity of SHP is modulated by bile acids, FGF15/19, and its ligands may reveal novel molecular targets for treating metabolic disorders. PUBLIC HEALTH RELEVANCE: Excess amounts of cholesterol and bile acids are associated with metabolic diseases, such as atherosclerosis and cholestatic liver disease. Bile acids cause an increase in the amount of small heterodimer partner (SHP) in liver cells which then inhibits the breakdown of cholesterol to bile acids. The overall aim of this project is to understand how cholesterol and bile acid levels are regulated by SHP. It is known that bile acids increase the synthesis of SHP, but it is not known whether the stability and activity of SHP are also affected by bile acids. These studies will examine whether and how bile acids and bile acid-induced intestinal FGF-19, and a potential SHP ligand, 3-Cl-AHPC, affect the stability and activity of SHP in liver cells. These studies will help us understand how SHP activity is modulated and may suggest new approaches for treating metabolic diseases.