Bile acid signaling plays a critical role in control of liver metabolism and inflammation. Accumulation of toxic bile acids causes liver inflammation and contributes to pathogenesis of chronic non-alcoholic fatty liver disease (NAFLD), diabetes and obesity. The rate of bile acid synthesis is regulated by the first and rate- limiting enzyme, cholesterol 7?-hydroxylase (CYP7A1), whereas bile acid composition is regulated by sterol 12?-hydroxylase (CYP8B1) in cholic acid synthesis. Bile acids activate a nuclear receptor FXR and a G protein coupled receptor TGR5 to regulate lipid, glucose and energy metabolism. It has been proposed that FXR plays a key role in bile acid feedback inhibition of bile acid synthesis. The anti-inflammatory action of bile acids has been recognized recently. However, the underlying molecular mechanisms of bile acid regulation of hepatic metabolic homeostasis and inflammation are not understood. Type 2 diabetes patients have higher serum 12?-hydroxylated bile acids, which is correlated to insulin resistance and dyslipidemia.
Three specific aims are designed to test the hypothesis that FXR and TGR5 signaling regulate bile acid synthesis and composition, which affect hepatic inflammation, insulin resistance, NAFLD and obesity.
Specific aim 1 is to study the mechanisms of FXR and TGR5 signaling in bile acid metabolism. FXR-/-, TGR5-/- and FXR/TGR5 double knockout (DK) mice will be used to test the hypothesis that the FXR/TGR5/CYP8B1 pathway may play a role in regulation of bile acid synthesis and lipid metabolism.
Specific aim 2 is to study TGR5 and FXR signaling in anti-inflammation in hepatocytes. Activation of FXR and TGR5 signaling may affect macrophage polarization to reduce hepatic inflammation. TGR5-/-, FXR-/- and FXR/TGR5 DK mice will be used to study the mechanisms of anti-inflammatory action of FXR and TGR5.
Specific aim 3 is to study nutrient regulation of the diurnal rhythm and fasting/restricted feeding on bile acid synthesis in NAFLD, insulin resistance and obesity. Fasting and restricted feeding and high fat diet affect the circadian rhythm of bile acid synthesis and energy metabolism. Experiments are designed to study the role of CYP8B1 in dyslipidemia, insulin resistance and NAFLD. This study is highly significant in elucidating the molecular mechanisms of regulation of bile acid synthesis and lipid homeostasis, and pathogenesis of liver-related metabolic diseases. Results from this study will have potential for developing drug therapies to improve insulin sensitivity, liver inflammation, hepatic steatosis, diabetes and obesity.

Public Health Relevance

Bile acids play critical roles in regulation of lipid, glucose, and energy homeostasis, and disruption of bile acid signaling causes dyslipidemia, fatty liver diseases, diabetes, and obesity. This renewal application will study the role of CYP8B1, a key regulatory gene in cholic acid synthesis pathway, in dyslipidemia and diabetes using several novel mouse models. This study will accelerate our knowledge on pathogenesis of and therapeutics for treatment of liver diseases, diabetes and obesity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK044442-18
Application #
8758723
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Sherker, Averell H
Project Start
1997-09-30
Project End
2018-05-31
Budget Start
2014-07-01
Budget End
2015-05-31
Support Year
18
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Northeast Ohio Medical University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
City
Rootstown
State
OH
Country
United States
Zip Code
44272
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Liu, Hailiang; Pathak, Preeti; Boehme, Shannon et al. (2016) Cholesterol 7α-hydroxylase protects the liver from inflammation and fibrosis by maintaining cholesterol homeostasis. J Lipid Res 57:1831-1844
Donepudi, Ajay C; Boehme, Shannon; Li, Feng et al. (2016) G-protein-coupled bile acid receptor plays a key role in bile acid metabolism and fasting-induced hepatic steatosis in mice. Hepatology :
Qi, Yunpeng; Jiang, Changtao; Cheng, Jie et al. (2015) Bile acid signaling in lipid metabolism: metabolomic and lipidomic analysis of lipid and bile acid markers linked to anti-obesity and anti-diabetes in mice. Biochim Biophys Acta 1851:19-29
Chiang, John Y L (2015) Sphingosine-1-phosphate receptor 2: a novel bile acid receptor and regulator of hepatic lipid metabolism? Hepatology 61:1118-20
Ferrell, Jessica M; Chiang, John Y L (2015) Short-term circadian disruption impairs bile acid and lipid homeostasis in mice. Cell Mol Gastroenterol Hepatol 1:664-677
Li, Tiangang; Chiang, John Y L (2015) Bile acids as metabolic regulators. Curr Opin Gastroenterol 31:159-65
Chiang, John Y L (2015) Negative feedback regulation of bile acid metabolism: impact on liver metabolism and diseases. Hepatology 62:1315-7
Ferrell, Jessica M; Chiang, John Y L (2015) Circadian rhythms in liver metabolism and disease. Acta Pharm Sin B 5:113-22
Zhang, Yaochen; Kim, Don-Kyu; Lee, Ji-Min et al. (2015) Orphan nuclear receptor oestrogen-related receptor γ (ERRγ) plays a key role in hepatic cannabinoid receptor type 1-mediated induction of CYP7A1 gene expression. Biochem J 470:181-93

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