Cholesterol is a critical nutrient that is required as a structural component of cell membranes and is a precursor in the biosynthesis of steroid hormones and bile acids. It is important that cholesterol levels are properly regulated because aberrant metabolism causes molecular defects in development and neurological function, and contributes to obesity, diabetes, atherosclerosis, and cancer. Thus, a fundamental understanding of cholesterol metabolism is key to mechanisms that underlie many of the major diseases of modern society. This proposal is focused on one aspect of the regulation of cholesterol, its conversion into bile acids. In preliminary studies, partly included in a recent publication, we have uncovered a novel role for the transcriptional co-activator PGC-1alpha in converting bile acids. PGC-1a is up-regulated during diabetes and fasting. A key role for PGC-1alpha in both diabetes and bile acid metabolism would provide a new link between cholesterol metabolism and diabetes. Our studies have shown that the gene for the rate controlling enzyme of the classic bile acid pathway, CYP7A1, is also up-regulated along with PGC-1alpha during fasting and in an animal model of type I diabetes. Our central hypothesis is that PGC-1alpha links bile acid metabolism with diabetes and we are evaluating the molecular mechanism for this association. Here, we plan to use both pharmacological and genetic manipulation to evaluate PGC-1alpha in regulation of CYP7A1 expression, bile acid metabolism, and hepatic glucose metabolism.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK071021-06S1
Application #
8152616
Study Section
Special Emphasis Panel (ZRG1-EMNR-F (03))
Program Officer
Margolis, Ronald N
Project Start
2010-06-01
Project End
2010-12-31
Budget Start
2010-06-01
Budget End
2010-12-31
Support Year
6
Fiscal Year
2010
Total Cost
$11,000
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Shin, Dong-Ju; Joshi, Pujan; Hong, Seung-Hyun et al. (2012) Genome-wide analysis of FoxO1 binding in hepatic chromatin: potential involvement of FoxO1 in linking retinoid signaling to hepatic gluconeogenesis. Nucleic Acids Res 40:11499-509
Chong, Hansook Kim; Biesinger, Jacob; Seo, Young-Kyo et al. (2012) Genome-wide analysis of hepatic LRH-1 reveals a promoter binding preference and suggests a role in regulating genes of lipid metabolism in concert with FXR. BMC Genomics 13:51
Jeon, Tae-Il; Osborne, Timothy F (2012) SREBPs: metabolic integrators in physiology and metabolism. Trends Endocrinol Metab 23:65-72
Jeon, Tae-Il; Seo, Young-Kyo; Osborne, Timothy F (2011) Gut bitter taste receptor signalling induces ABCB1 through a mechanism involving CCK. Biochem J 438:33-7
Chong, Hansook Kim; Infante, Aniello M; Seo, Young-Kyo et al. (2010) Genome-wide interrogation of hepatic FXR reveals an asymmetric IR-1 motif and synergy with LRH-1. Nucleic Acids Res 38:6007-17
Shin, Dong-Ju; Osborne, Timothy F (2009) FGF15/FGFR4 integrates growth factor signaling with hepatic bile acid metabolism and insulin action. J Biol Chem 284:11110-20
Osborne, Timothy F; Espenshade, Peter J (2009) Evolutionary conservation and adaptation in the mechanism that regulates SREBP action: what a long, strange tRIP it's been. Genes Dev 23:2578-91
Shin, Dong-Ju; Osborne, Timothy F (2008) Peroxisome proliferator-activated receptor-gamma coactivator-1alpha activation of CYP7A1 during food restriction and diabetes is still inhibited by small heterodimer partner. J Biol Chem 283:15089-96
Matsukuma, Karen E; Wang, Li; Bennett, Mary K et al. (2007) A key role for orphan nuclear receptor liver receptor homologue-1 in activation of fatty acid synthase promoter by liver X receptor. J Biol Chem 282:20164-71
Matsukuma, Karen E; Bennett, Mary K; Huang, Jiansheng et al. (2006) Coordinated control of bile acids and lipogenesis through FXR-dependent regulation of fatty acid synthase. J Lipid Res 47:2754-61

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