Bile acid synthesis is regulated by cholesterol 7alpha-hydroxylase (CYP7A1), the rate-limiting enzyme of the pathway, and sterol 12alpha-hydroxylase (CYP8B1) that catalyzes cholic acid (CA) synthesis and regulates the ratio of CA to chenodeoxycholic acid (CDCA) in bile. Transcription of the CYP7A1 and CYP8B1 is feedback inhibited by bile acids. We hypothesize that a nuclear receptor-mediated mechanism may be involved in regulation of genes in bile acid synthesis. CDCA has been shown to activate a nuclear hormone receptor, farnesoid X receptor (FXR) and induce a negative nuclear receptor, short heterodimer partner (SHP). SHP interacts with either alpha-fetoprotein transcription factor (FTF) and/or hepatocyte nuclear factor4 (HNF4) and represses CYP7A1 transcription. We hypothesize that similar mechanism may regulate CYP8B1 transcription but FTF and HNF4 differentially mediate FXR-dependent bile acid inhibition. Cholesterol stimulates CYP7A1 transcription by activating oxysterol receptor LXR only in the mouse model. In contrast, cholesterol inhibits human CYP7A1 and CYP8B1 transcription. We hypothesize that sterol response element binding proteins (SREBPs) that are known to stimulate sterol-suppressed genes also regulate the CYP7A1 and CYP8B1.
The specific aims of this research proposal are to use site-directed mutagenesis, promoter/reporter assays, and electrophoretic mobility shift assays to study bile acid regulation of CYP7A1 and CYP8B1 transcription by FTF and HNF4, and sterol regulation of these genes by SREBP-1c, and to identify bile acid and sterol response elements in the promoters. Our long-term objective is to study the mechanisms of bile acid synthesis and regulation and cholesterol homeostasis by nuclear receptors and SREBPs. Information obtained from this project is important for elucidation the molecular mechanism of human diseases such as atherosclerosis, cholestatic liver diseases and gallstone disease, and for developing new drug therapies targeted to nuclear receptors for lowering cholesterol by stimulating bile acid synthesis, secretion and transport.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK058379-15A2
Application #
6430154
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Serrano, Jose
Project Start
1983-03-01
Project End
2007-01-31
Budget Start
2002-04-01
Budget End
2003-01-31
Support Year
15
Fiscal Year
2002
Total Cost
$278,200
Indirect Cost
Name
Northeast Ohio Medical University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Rootstown
State
OH
Country
United States
Zip Code
44272
Chiang, John Y L; Ferrell, Jessica M (2018) Bile Acid Metabolism in Liver Pathobiology. Gene Expr 18:71-87
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 (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
Liu, Hailiang; Pathak, Preeti; Boehme, Shannon et al. (2016) Cholesterol 7?-hydroxylase protects the liver from inflammation and fibrosis by maintaining cholesterol homeostasis. J Lipid Res 57:1831-1844
Ferrell, Jessica M; Boehme, Shannon; Li, Feng et al. (2016) Cholesterol 7?-hydroxylase-deficient mice are protected from high-fat/high-cholesterol diet-induced metabolic disorders. J Lipid Res 57:1144-54

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