Cytochrome P450-Endogenous Substrate Metabolism

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The long-range goal of this project is to elucidate the endocrine regulation of hepatic cytochromes P450 (Cyps) and other enzymes that metabolize steroid hormones, bile acids, carcinogens and other lipophilic substrates of medical or environmental importance, with a focus on the actions of growth hormone (GH), a pituitary polypeptide hormone. The proposed project period uses the mouse as a model system to investigate the molecular mechanisms by which GH and its sex-dependent ultradian secretory patterns regulate Cyps and many other liver-expressed genes in a sex-specific manner. The major objective of this project is to elucidate the mechanisms that underpin the dependence of sex-specific liver gene expression on STAT5b, a signal transducer and activator of transcription that is directly activated by each incoming adult male plasma GH pulse, and on HNF41, a liver-enriched transcription factor. The studies proposed will test the hypothesis that the actions of STAT5b and HNF41 on sex-specific Cyps and other GH pulse-responsive genes involve both direct and indirect mechanisms operating through a complex regulatory network. Genome-wide approaches will be used to elucidate key components and features of the overall network through the discovery of 1) novel primary targets of GH-activated STAT5b, 2) epigenetic regulatory mechanisms controlled by GH that may lead to long-term gene silencing, and 3) transcription factors that act proximal to downstream Cyp genes. Together, these studies will elucidate key features of the intracellular events that determine the complex, GH-dependent patterns of expression of hepatic Cyps, which control metabolic processes having a major impact on liver physiology and human health, including steroid hormone metabolism, cholesterol catabolism, drug biotransformation and carcinogen activation.