Obesity has become a global epidemic and greatly increases the risk for diabetes, cardiovascular disease, and non-alcoholic fatty liver disease (NAFLD). Nearly 80% of obese people develop NAFLD, which progresses to steatohepatitis (NASH) and further to end-stage liver diseases, such as fibrosis, cirrhosis, and liver cancer, but good therapeutic options to treat NAFLD are not available. The hallmark of NAFLD is abnormal accumulation of triglyceride (TG) in the liver due to dysregulated lipid metabolism. Bile acids (BAs) are recently recognized signaling molecules that profoundly impact metabolism and counteract obesity. The BA-induced intestinal hormone, FGF15/19 (mFGF15. hFGF19), has received great attention because its lipid-lowering and insulin-sensitizing effects and, thus, its therapeutic potential in treating obesity and diabetes. However, little is known about how FGF15/19 controls lipid metabolism. The overall goal of this application is to determine how an orphan nuclear receptor Small Heterodimer Partner (SHP, NR0B2) mediates postprandial actions of FGF15/19 by epigenetic regulation of hepatic lipid metabolism. We have preliminary data showing that FGF19 treatment induced recruitment of DNA methyltransferase-3a (DNMT3a) to key lipogenic genes in a SHP-dependent manner, and liver-specific downregulation of SHP or DNMT3a led to decreased 5-methyl cytosine (5mC) DNA levels at these genes and increased liver TG levels, suggesting a novel function of SHP and DNMT3a in hepatic lipogenesis. Based these exciting preliminary data, we hypothesize that SHP physiologically mediates epigenetic repression of hepatic lipogenesis by recruiting DNMT3a, in response to FGF15 signaling in the late fed-state, but this FGF15- SHP-DNMT3a regulatory axis is disrupted in obesity. To test this hypothesis, we will 1) determine the role and the underlying mechanisms of how the FGF15-SHP-DNMT3a regulatory axis mediates epigenetic repression of hepatic lipogenic genes, and then, 2) investigate the in vivo function of hepatic SHP and DNMT3a in regulation of liver lipid metabolism, focusing on de novo lipogenesis, and dysregulation of this regulatory axis in obesity in mice and determine human relevance by analysis of liver samples from NAFLD patients. To achieve these goals, multifaceted approaches, including molecular/biochemical, metabolic, and epigenetic studies and global genomic analyses, will be utilized in SHP-LKO and FGF15-KO mice, and mouse models generated by viral-mediated expression and downregulation of proteins. Impact: Our expertise on transcriptional and epigenetic control of liver lipid metabolism by nuclear receptors uniquely qualifies us to carry out this project. This proposal will test whether SHP and DNMT3a mediate FGF15/19 actions in hepatic lipid metabolism, and may reveal effective approaches for developing new therapeutic targets for NAFLD and diagnostic biomarkers to monitor its progression.

Public Health Relevance

Obesity is a rapidly growing global epidemic and greatly increases the risk for diabetes, cardiovascular disease, and non-alcoholic fatty liver diseases (NAFLD). Nearly 80% of obese people develop NAFLD, which progresses to steatohepatitis and further to fatal end-stage liver diseases, such as fibrosis, cirrhosis, and liver cancer, but good therapeutic options to treat these obesity-related liver diseases are not available. This proposal will determine the role of SHP and DNMT3a in mediating lipid-lowering metabolic actions of a late fed-state hormone FGF15/19 in epigenetic regulation of liver lipid metabolism and may reveal novel approaches for clinical intervention in for NAFLD and other obesity-related metabolic diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK062777-15
Application #
9453671
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Silva, Corinne M
Project Start
2003-08-01
Project End
2022-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
15
Fiscal Year
2018
Total Cost
Indirect Cost
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
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Byun, Sangwon; Kim, Young-Chae; Zhang, Yang et al. (2017) A postprandial FGF19-SHP-LSD1 regulatory axis mediates epigenetic repression of hepatic autophagy. EMBO J 36:1755-1769
Choi, Sung E; Kwon, Sanghoon; Seok, Sunmi et al. (2017) Obesity-Linked Phosphorylation of SIRT1 by Casein Kinase 2 Inhibits Its Nuclear Localization and Promotes Fatty Liver. Mol Cell Biol 37:
Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222
Fu, Ting; Kim, Young-Chae; Byun, Sangwon et al. (2016) FXR Primes the Liver for Intestinal FGF15 Signaling by Transient Induction of ?-Klotho. Mol Endocrinol 30:92-103
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
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
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

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