Conversion of cholesterol to bile acids in the liver is the major pathway for disposal of cholesterol in mammals. Recent studies have shown that bile acids not only are the physiological detergents that facilitate the absorption, transport and distribution of lipid-soluble vitamins and dietary fats, but also are the signaling molecules that activate nuclear receptors; farnesoid X receptor (FXR), pregnane X receptor (PXR) and vitamin D3 receptor (VDR). Bile acid feedback inhibits bile acid synthesis by suppressing the gene encoding the rate-limiting enzyme of the classic bile acid biosynthetic pathway, cholesterol 7alpha-hydroxylase (CYP7A1). It has been suggested that FXR induces a negative nuclear receptor, small heterodimer partner (SHP), which subsequently inhibits CYP7A1 gene transcription. Bile acids also induce inflammatory cytokines, which activate the MAP kinase/JNK signaling pathways to inhibit CYP7A1 gene transcription. Sterol 27-hydroxylase (CYP27A) catalyzes sterol side-chain oxidation of the classic pathway and initiates the alternative bile acid synthesis pathway. CYP27A1 also catalyzes VD3 synthesis in the liver, intestine and kidney. Oxysterol 7alpha-hydroxylase (CYP7B1) plays roles in steroid and oxysterol metabolisms, in addition to bile acid synthesis. This project will study regulation of the human CYP7A1, CYP27A1, and CYP7B1 genes by bile acids and steroids. Molecular biology techniques including small interference RNA, reporter gene assay, site-directed mutagenesis, electrophoretic mobility shift assays, mammalian two-hybrid assay, and real time PCR will be used to study gene regulation.
Specific aim 1 will study the mechanism of bile acid inhibition by PXR, VDR, and MAP kinase/JNK pathways.
Specific aim 2 will study the mechanism of cytokine and VDR regulation of the CYP27A1 gene.
Specific aim 3 will study regulation of the CYP7B1 gene by steroid response element binding proteins (SREBP) and estrogen receptor (ER). The long-term objective of this research project is to understand the molecular mechanisms of regulation of bile acid synthesis and steroid metabolism, and to elucidate the mechanism of human diseases such as cholestatic liver diseases, gallstone disease, atherosclerosis, and diabetes. Drug therapies targeted to the nuclear receptors involved in regulation of bile acid synthesis genes could be developed based on this research for lowering serum cholesterol and treating cardiovascular and liver diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK044442-12
Application #
7222001
Study Section
Special Emphasis Panel (ZRG1-GMA-3 (01))
Program Officer
Serrano, Jose
Project Start
1997-09-30
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
12
Fiscal Year
2007
Total Cost
$232,320
Indirect Cost
Name
Northeast Ohio Medical University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
077779882
City
Rootstown
State
OH
Country
United States
Zip Code
44272
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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