Regulation of cholesterol catabolism by bile acids

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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.