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.
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