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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK062777-09
Application #
8247128
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Margolis, Ronald N
Project Start
2002-12-01
Project End
2013-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
9
Fiscal Year
2012
Total Cost
$289,414
Indirect Cost
$97,559
Name
University of Illinois Urbana-Champaign
Department
Physiology
Type
Schools of Arts and Sciences
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
Fu, T; Kemper, J K (2016) MicroRNA-34a and Impaired FGF19/21 Signaling in Obesity. Vitam Horm 101:175-96
Kim, Dong-Hyun; Kwon, Sanghoon; Byun, Sangwon et al. (2016) Critical role of RanBP2-mediated SUMOylation of Small Heterodimer Partner in maintaining bile acid homeostasis. Nat Commun 7:12179
Fu, Ting; Kim, Young-Chae; Byun, Sangwon et al. (2016) FXR Primes the Liver for Intestinal FGF15 Signaling by Transient Induction of β-Klotho. Mol Endocrinol 30:92-103
Kim, Dong-Hyun; Xiao, Zhen; Kwon, Sanghoon et al. (2015) A dysregulated acetyl/SUMO switch of FXR promotes hepatic inflammation in obesity. EMBO J 34:184-99
Kim, Young-Chae; Byun, Sangwon; Zhang, Yang et al. (2015) Liver ChIP-seq analysis in FGF19-treated mice reveals SHP as a global transcriptional partner of SREBP-2. Genome Biol 16:268
Kim, Young-Chae; Fang, Sungsoon; Byun, Sangwon et al. (2015) Farnesoid X receptor-induced lysine-specific histone demethylase reduces hepatic bile acid levels and protects the liver against bile acid toxicity. Hepatology 62:220-31
Fu, Ting; Seok, Sunmi; Choi, Sunge et al. (2014) MicroRNA 34a inhibits beige and brown fat formation in obesity in part by suppressing adipocyte fibroblast growth factor 21 signaling and SIRT1 function. Mol Cell Biol 34:4130-42
Seok, Sunmi; Fu, Ting; Choi, Sung-E et al. (2014) Transcriptional regulation of autophagy by an FXR-CREB axis. Nature 516:108-11
Smith, Zachary; Ryerson, Daniel; Kemper, Jongsook Kim (2013) Epigenomic regulation of bile acid metabolism: emerging role of transcriptional cofactors. Mol Cell Endocrinol 368:59-70
Seok, Sunmi; Kanamaluru, Deepthi; Xiao, Zhen et al. (2013) Bile acid signal-induced phosphorylation of small heterodimer partner by protein kinase Cζ is critical for epigenomic regulation of liver metabolic genes. J Biol Chem 288:23252-63

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