The rate of cholesterol degradation is tightly regulated in vivo. The major metabolic pathway for the degradation of cholesterol is via conversion to bile acids. The end-products of this pathway, the bile acids, are negative regulators of cholesterol degradation. This is an important feedback loop that regulates cholesterol homeostasis. Recent evidence indicates that the nuclear receptor FXR is a bile acid receptor that may be involved in this process. This proposal will involve a detailed analysis of the role of FXR in regulating cholesterol homeostasis. This will include a detailed description of the precise signaling molecules that bind to FXR and an analysis of the target genes that are modulated by this receptor. The mechanism of FXR activation or repression of gene expression will also be studied. Finally, the physiological function of FXR ligands will be studied through a combination of pharmacologic and genetic approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK057636-02
Application #
6381792
Study Section
Endocrinology Study Section (END)
Program Officer
Margolis, Ronald N
Project Start
2000-07-01
Project End
2005-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
2
Fiscal Year
2001
Total Cost
$357,000
Indirect Cost
Name
City of Hope/Beckman Research Institute
Department
Type
DUNS #
City
Duarte
State
CA
Country
United States
Zip Code
91010
Li, Hai; Chen, Frank; Shang, Quan et al. (2005) FXR-activating ligands inhibit rabbit ASBT expression via FXR-SHP-FTF cascade. Am J Physiol Gastrointest Liver Physiol 288:G60-6
Xu, Guorong; Li, Hai; Pan, Lu-Xing et al. (2003) FXR-mediated down-regulation of CYP7A1 dominates LXRalpha in long-term cholesterol-fed NZW rabbits. J Lipid Res 44:1956-62
Dussault, Isabelle; Beard, Rick; Lin, Min et al. (2003) Identification of gene-selective modulators of the bile acid receptor FXR. J Biol Chem 278:7027-33
Xu, Guorong; Pan, Lu-xing; Erickson, Sandra K et al. (2002) Removal of the bile acid pool upregulates cholesterol 7alpha-hydroxylase by deactivating FXR in rabbits. J Lipid Res 43:45-50
Xu, Guorong; Pan, Lu-Xing; Li, Hai et al. (2002) Regulation of the farnesoid X receptor (FXR) by bile acid flux in rabbits. J Biol Chem 277:50491-6