Regulation of cholesterol catabolism by bile acids

描述（由申请人提供）：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。该项目的总体目标是了解胆固醇和胆汁酸水平是如何通过孤儿核受体和转录抑制因子小异源二聚体伴侣（SHP）进行调节的，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代表了从体内消除胆固醇的主要途径，胆固醇71羟化酶（CYP 7A 1）在此过程中起着关键作用。胆汁酸通过激活多种信号传导途径反馈抑制CYP 7A 1的转录，包括胆汁酸受体FXR的SHP诱导、细胞激酶信号传导和FGF 15/19肠-肝信号传导途径，并且SHP已被认为是所有这些抑制途径中的关键下游调节剂。在初步研究中，我们已经获得了支持这一假设的数据，即胆汁酸不仅诱导SHP表达，而且通过抑制蛋白酶体降解和通过上游磷酸化事件增加SHP的SUMO化来增加SHP的稳定性和活性。此外，我们建议，SHP的稳定性和活性也受到潜在的激动剂，3-Cl-AHPC。为了验证这些假设，我们将：1）确定SHP的泛素化-蛋白酶体降解在胆汁酸信号转导中的作用。2)研究SHP类小泛素化在SHP阻遏活性中的作用。3)阐明3-Cl-AHPC对肝细胞内SHP活性和稳定性的调节作用。由于SHP在正常生理学和疾病过程中起着关键作用，因此我们的研究确定了SHP的肝脏活性如何受到胆汁酸，FGF 15/19及其配体的调节，这可能会揭示治疗代谢紊乱的新分子靶点。公共卫生相关性：过量的胆固醇和胆汁酸与代谢疾病有关，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异二聚体伴侣（SHP）的量增加，然后抑制胆固醇分解为胆汁酸。这个项目的总体目标是了解胆固醇和胆汁酸水平是如何由SHP调节的。已知胆汁酸增加SHP的合成，但尚不清楚SHP的稳定性和活性是否也受胆汁酸的影响。这些研究将检查胆汁酸和胆汁酸诱导的肠道FGF-19以及潜在的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.