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My lab studies orphan nuclear receptor-mediated regulation of genes encoding drug metabolizing enzymes and transporters.The same enzymes and transporters are also responsible for the metabolism and homeostasis of endogenous chemicals (endobiotics) that include steroid hormones, cholesterol, glucose, lipids, bile acids and bilirubin.Research in my lab has helped to establish members of the orphan nuclear receptors, such as PXR (pregnane X receptor), CAR (constitutive androstane receptor),LXR (liver X receptor), FXR (farnesoid X receptor) and ROR (retinoid-related orphan receptor), as xeno-and endo-sensors that sense xeno-and endobiotics which, in turn, lead to enzyme and transporter gene regulation.This regulation has broad implications in drug metabolism and drug development.Moreover, these orphan receptors and their target enzymes can be explored as therapeutic targets for the treatment and prevention of human diseases, such as cholestasis, jaundice, gallstone disease, breast cancer, prostate cancer, colon cancer, and metabolic syndrome.To better understand the transcriptional regulation of enzymes and transporters and the significance of this regulation in vivo, my lab has created a wide array of genetic engineered mice with compromised (gene knockout), heightened (transgenic), or humanized receptor activities.This presentation will focus on our recent work in understanding the endobiotic role of the Phase Ⅱ enzymes estrogen sulfotransferases (EST/SULT1E1) and cholesterol sulfotransferase (SULT2B 1 b) in obesity, insulin resistance and Type 2 diabetes.