The goal of this proposal is to explore the novel role of the retinoid-related orphan receptors (RORs) in the regulation of the human hydroxysteroid sulfotransferase SULT2A1, a Phase II enzyme important for the metabolism of bile acids and many other xenobiotics and endobiotics. RORs were previously known to play a role in tissue development and circadian rhythm. Among three ROR isoforms, ROR? and ROR? are expressed in the liver, but their hepatic function remains unknown. It has recently been reported that certain hepatic CYP enzymes, such as CYP7B1 and CYP2C8, can be transcriptionally regulated by RORs, suggesting a broader role of these orphan receptors in xeno- and endobiotic enzyme regulation. Our preliminary results showed that: 1) The expression of ROR? was negatively correlated to the expression of SULT2A1 in primary human hepatocytes;2) Overexpression of ROR? inhibited the expression of endogenous SULT2A1 in HepG2 cells;3) A ROR response element (RORE) has been identified in the SULT2A1 gene promoter that overlaps a CAR response element (CARE) on the same promoter;and 4) The positive regulation of SULT2A1 gene promoter by CAR was inhibited by the co-transfection of ROR?. Based on our preliminary data, we hypothesize that ROR? and/or ROR? have a previously unrecognized role in the regulation of the human hydroxysteroid sulfotransferase SULT2A1. Specifically, we hypothesize that: 1) The expression of ROR? and/or ROR? is negatively correlated to the expression of SULT2A1 in the human liver;and 2) The human SULT2A1 gene promoter is a transcriptional target of RORs. We propose two specific aims to test our hypotheses: (1) To determine whether the expression of ROR? and ROR? correlates to the expression of SULT2A1 in the human liver;and (2) To determine the molecular mechanism by which ROR? and ROR? regulate the expression of SULT2A1 gene. To our knowledge, this study represents the first attempt to systematically evaluate the novel function of ROR? and ROR? in regulating hepatic drug metabolizing enzymes in humans. SULT2A1-mediated bile acid sulfation and detoxification play an important role in the prevention and relief of cholestasis. Results from this study may help to understand the role of RORs in the interindividual variation of SULT2A1 gene expression and the propensity to cholestasis in patients. RORs were previously known for their roles in tissue development and circadian rhythm. The current application represents an innovative and paradigm-shifting project that meets the missions of the NIH R21 Exploratory Developmental Research Grant Program.

Public Health Relevance

This application addresses the regulation of the human hydroxysteroid sulfotransferase (SULT2A1), a Phase II drug-metabolizing enzyme, by the retinoid-related orphan receptors (RORs). RORs are previously known for their roles in tissue development and circadian rhythm, the current application represents an innovative and paradigm-shifting project that meets the missions of the NIH R21 Exploratory Developmental Research Grant Program. SULT2A1 is important for the metabolism of bile acids and relief of cholestasis. Results from this study may help to understand the role of RORs in the interindividual variation of SULT2A1 gene expression and the propensity to cholestasis in patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21ES019629-02
Application #
8210824
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Shreffler, Carol K
Project Start
2011-01-01
Project End
2012-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
2
Fiscal Year
2012
Total Cost
$227,250
Indirect Cost
$77,250
Name
University of Pittsburgh
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Jiang, Mengxi; Xie, Wen (2013) Role of the constitutive androstane receptor in obesity and type 2 diabetes: a case study of the endobiotic function of a xenobiotic receptor. Drug Metab Rev 45:156-63
Kittayaruksakul, Suticha; Zhao, Wenchen; Xu, Meishu et al. (2013) Identification of three novel natural product compounds that activate PXR and CAR and inhibit inflammation. Pharm Res 30:2199-208
Ou, Zhimin; Shi, Xiongjie; Gilroy, Richard K et al. (2013) Regulation of the human hydroxysteroid sulfotransferase (SULT2A1) by ROR? and ROR? and its potential relevance to human liver diseases. Mol Endocrinol 27:106-15
He, Jinhan; Gao, Jie; Xu, Meishu et al. (2013) PXR ablation alleviates diet-induced and genetic obesity and insulin resistance in mice. Diabetes 62:1876-87
Swanson, Hollie I; Wada, Taira; Xie, Wen et al. (2013) Role of nuclear receptors in lipid dysfunction and obesity-related diseases. Drug Metab Dispos 41:1-11
Chai, Xiaojuan; Zeng, Su; Xie, Wen (2013) Nuclear receptors PXR and CAR: implications for drug metabolism regulation, pharmacogenomics and beyond. Expert Opin Drug Metab Toxicol 9:253-66
Gao, Jie; He, Jinhan; Shi, Xiongjie et al. (2012) Sex-specific effect of estrogen sulfotransferase on mouse models of type 2 diabetes. Diabetes 61:1543-51
Saini, Simrat P S; Zhang, Bin; Niu, Yongdong et al. (2011) Activation of liver X receptor increases acetaminophen clearance and prevents its toxicity in mice. Hepatology 54:2208-17