Abstract

3URJUDP'LUHFWRU3ULQFLSDO,QYHVWLJDWRU /DVW)LUVW0LGGOH Chiang, John Y. L. 352-(&76800$5< 6HHLQVWUXFWLRQV Type 2 diabetes and obesity is associated with dyslipidemia, hyperglycemia and insulin resistance. Hepatic steatosis contributes to insulin resistance and non-alcoholic fatty liver disease. Bile acids play a key role in regulation of lipid, glucose and energy metabolism by activating a nuclear hormone receptor FXR, and G protein-coupled receptor TGR5. Our central hypothesis is that nutrients, growth hormone, circadian rhythm and gut microbiota regulate bile acid synthesis to maintain metabolic homeostasis, and impairment of this regulatory response contributes to dyslipidemia, glucose intolerance, insulin resistance, fatty liver disease and obesity.
Specific aim 1 will study the role of bile acid receptor signaling in regulation of hepatic metabolism. The mechanism of growth hormone-STAT5 regulation of bile acid synthesis and a male predominant Cyp7b1 will be studied using reporter assay and chromatin immuno- precipitation assay to identify STAT5 binding sites and epigenetic regulation of Cyp7b1 promoter by STAT5. Tgr5-/-, Cyp7a1-/- and adenovirus-Cyp8b1 over-expressed mice with different bile acid composition and Cyp7a1, Cyp8b1 and cyp7b1 expression will be used to study growth hormone regulation.
Specific aim 2 will study the role of bile acid receptor signaling in fatty liver, insulin resistance and diabetes. The mechanism of FXR and TGR5 in GLP-1 secretion and glucose metabolism will be studied. Tgr5-/- mice will be used to study effect of vertical sleeve gastrectomy on improving insulin resistance, dyslipidemia and microbiome before and after surgery.
Specific aim 3 will study circadian rhythm of bile acid synthesis in metabolic homeostasis. The liver-gut microbiota axis plays a critical role in bile acid metabolism and disturbance of circadian rhythm is linked to metabolic diseases. Dysbiosis is associated with obesity, and inflammatory bowel diseases. Tgr5-/-, FXR-/- and Cyp7a1-/- with different bile acid pool size and/or composition will be used for time-restricted feeding of Western high fat/high cholesterol diet to study bile acid metabolism and gut microbiome by RNA sequencing. Cyp7a1-/-, Fxr-/-, and Tgr5-/- will be used to determine how time-restricted feeding in day time or night time affect affect hepatic gene rhythms and overall bile acid homeostasis. 5(/(9$1&( 6HHLQVWUXFWLRQV Understanding the underlying molecular mechanism of bile acid signaling in liver metabolism and inflammation is critical for developing bile acid-based therapeutic drugs for treating metabolic liver diseases. Study liver to gut axis and circadian disruption on gut microbiome and bile acid metabolism, and the role of TGR5 signaling on diabetes remission after gastric bypass is highly relevant to liver diseases and treatment. 352-(&73(5)250$1&(6,7( 6 LIDGGLWLRQDOVSDFHLVQHHGHGXVH3URMHFW3HUIRUPDQFH6LWH)RUPDW3DJH

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK058379-30
Application #
9250119
Study Section
Special Emphasis Panel (NSS)
Program Officer
Burgess-Beusse, Bonnie L
Project Start
2016-05-01
Project End
2021-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
30
Fiscal Year
2017
Total Cost
Indirect Cost

  Institution

Name
Northeast Ohio Medical University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
077779882
City
Rootstown
State
OH
Country
United States
Zip Code
44272

  Publications

Donepudi, Ajay C; Ferrell, Jessica M; Boehme, Shannon et al. (2018) Deficiency of cholesterol 7?-hydroxylase in bile acid synthesis exacerbates alcohol-induced liver injury in mice. Hepatol Commun 2:99-112
Pathak, Preeti; Xie, Cen; Nichols, Robert G et al. (2018) Intestine farnesoid X receptor agonist and the gut microbiota activate G-protein bile acid receptor-1 signaling to improve metabolism. Hepatology 68:1574-1588
Chiang, John Y L; Ferrell, Jessica M (2018) Bile Acid Metabolism in Liver Pathobiology. Gene Expr 18:71-87
Chiang, John Y L (2017) Linking Sex Differences in Non-Alcoholic Fatty Liver Disease to Bile Acid Signaling, Gut Microbiota, and High Fat Diet. Am J Pathol 187:1658-1659
Chiang, John Y L (2017) Linking long noncoding RNA to control bile acid signaling and cholestatic liver fibrosis. Hepatology 66:1032-1035
Chiang, John Y L; Pathak, Preeti; Liu, Hailiang et al. (2017) Intestinal Farnesoid X Receptor and Takeda G Protein Couple Receptor 5 Signaling in Metabolic Regulation. Dig Dis 35:241-245
Chiang, John Y L (2017) Bile acid metabolism and signaling in liver disease and therapy. Liver Res 1:3-9
Pathak, Preeti; Liu, Hailiang; Boehme, Shannon et al. (2017) Farnesoid X receptor induces Takeda G-protein receptor 5 cross-talk to regulate bile acid synthesis and hepatic metabolism. J Biol Chem 292:11055-11069
Donepudi, Ajay C; Boehme, Shannon; Li, Feng et al. (2017) G-protein-coupled bile acid receptor plays a key role in bile acid metabolism and fasting-induced hepatic steatosis in mice. Hepatology 65:813-827
Chiang, John Y L (2017) Targeting bile acids and lipotoxicity for NASH treatment. Hepatol Commun 1:1002-1004

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