The overall goal of this project is to understand the role of bile acids as recently recognized key signaling molecules that control integrative metabolism and energy balance and the dysfunction of this regulatory pathway in obesity and related diseases. Obesity is a growing epidemic worldwide. Fatty liver (steatosis) that develops in obese people increases the risk for diabetes, heart disease, and even, liver cancer. The role of insulin in the regulation of metabolism has been extensively studied, but little is known about how BA signaling is integrated to control hepatic metabolism. Small Heterodimer Partner (SHP) has been implicated as a key player in BA signaling pathways. In response to bile acid signaling, SHP mediates the epigenetic repression of Cyp7a1, the rate-limiting bile acid biosynthetic gene, by coordinately recruiting histone-modifying proteins (histone methylases and deacetylases) to the promoter. Further, post-translational modifications (PTMs) of SHP itself regulates its level and activity in the liver. These previous studies, however, did not address the key questions of how the PTM of SHP and the epigenetic histone modifications are regulated in response to BA signaling and how this regulation is altered in pathology, such as fatty liver disease. Answering these questions is the specific goal of the current proposal. Surprisingly, preliminary studies have revealed a role for protein kinase C-zeta (PKC?) in regulating SHP activity in response to bile acid signaling by phosphorylating Thr-55 of SHP which is critical for SHP-repression activity and is a key event upstream of other known PTMs of SHP that control its stability and activity. Notably, PKC? is a negative regulator of obesity-induced inflammation and hepatic steatosis, thus, phosphorylation of SHP by PKC? may be critically involved in bile acid-regulated hepatic metabolism. Based on these studies, we hypothesize that SHP functions as a key epigenetic coordinator in bile acid-regulated hepatic metabolism and that bile acid signaling-induced PTMs of SHP, particularly phosphorylation by PKC?, are critical to its hepatic functions, but, in obesity, PTMs of SHP and SHP-mediated epigenetic regulation are dysregulated, contributing to abnormal hepatic metabolism. To test this hypothesis, we will utilize in vitro and in vivo studies using transgenic and obese mouse models, cultured hepatic cells, and human liver hepatocyes or tissue from normal or fatty liver disease patients.
Our specific aims are to: 1) define the role of PTMs of SHP induced by BA signaling (BA or FGF19) in normal hepatic metabolism, focusing on phosphorylation by PKC?? 2) determine whether SHP functions as a key epigenetic coordinator of bile acid responsive hepatic genes, including analyzing global genomic binding sites of SHP and bile acid-mediated epigenetic gene regulation, and 3) investigate whether PTMs of SHP, global SHP binding sites, and SHP-mediated epigenetic events are altered in fatty livers, contributing to metabolic abnormalities in obesity. These studies will elucidate how SHP epigenetically controls BA-regulated hepatic functions, and identify novel potential diagnostic and/or therapeutic targets for metabolic diseases.

Public Health Relevance

In obese people, fat and sugar levels are not properly controlled and extra fat is stored abnormally in liver (fatty liver), which puts obese people at a high risk for diabetes, heart disease, and even, liver cancer. In this proposal, we will focus on short heterodimer partner (SHP), a key mediator of the action of bile acids, which are recently recognized important, but understudied, regulators of fat and sugar levels in the body. Understanding how SHP mediates bile acid action in normal liver and its abnormal action in fatty liver will be important in developing new drugs for treatment of fatty liver and other obesity-related diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK062777-10
Application #
8506036
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Margolis, Ronald N
Project Start
2002-12-01
Project End
2017-03-31
Budget Start
2013-05-01
Budget End
2014-03-31
Support Year
10
Fiscal Year
2013
Total Cost
$334,759
Indirect Cost
$117,259
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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