The liver X receptors (LXRs), including the a and p isoforms, are highly expressed in the liver. LXRs can be activated by endogenous, natural, and synthetic ligands. Previous studies on LXRs have been focused on their roles in cholesterol and lipid homeostasis and inflammation. However, whether or not LXRs play a role in the regulation of xenobiotic enzymes and transporters and consequently impact the xeno- and endobiotic responses is unknown. Our preliminary results showed that transgenic mice expressing the activated LXRa (VP-LXRa) had an altered expression of multiple Phase I and Phase II enzymes, and possibly drug transporters. The most notable is the induction of the Phase II sulfotransferases (SULTs) in the VP-LXRa mice and LXR agonist-treated wild type mice. These include SULT2A9, a bile acid detoxifying hydroxysteroidsulfotransferase, and estrogen sulfotransferase (EST, orSULT1E1), which catalyzes the sulfation and deactivation of the estrogens. Promoter analysis strongly suggested SULT2A9 as a transcriptional target of LXRs. We also showed that the LXR a and p double knockout (LXR DKO) mice had decreased basal expression of SULT2A9. SULT2A1, the human homolog of SULT2A9, was induced in LXR agonist-treated primary human hepatocytes,suggesting that the SULT2A regulation may be conserved in humans. The induction of EST/SULT1E1 in the transgenic mice was associated with an inhibition of estrogen-induced uterine epithelial proliferation and estrogen receptor target gene expression. Based on our preliminary results, we hypothesize that the mouse and/or human SULTs are transcriptional targets of LXRs. A testable prediction is that the LXR-mediated activation of bile acid- and estrogen-metabolizing SULTs will lead to the alleviation of bile acid hepatotoxicity and cholestasis as well as down-regulation of estrogen activity in vivo. By using the "gain-of-function" VP-LXRa transgenic, "loss-of- function" LXR knockout and LXR ligand-treated wild type mice, we propose the following specific aims: (1) To determine whether the activation of LXRs alleviates bile acid hepatotoxicity and cholestasis;(2) To determine whether the activation of LXRs can functionally deprive estrogens;and (3) To determine the molecular basis by which LXRs regulate the mouse and human SULT2As and ESTs/SULT1E1s. These studies are expected to reveal a novel function for LXRs in protecting xeno- and endobiotic chemical challenges. We propose that LXRs have evolved to have dual function in maintaining cholesterol and bile acid homeostasis by increasing cholesterol catabolism;and, at the same time, preventing toxicity from bile acid accumulation. It is anticipated that the development of selective LXR agonists may represent a novel strategy to prevent cholestasis and limit estrogen activity in vivo. Since estrogens are prerequisites for breast cancer, delineating the regulatory effects of LXRs on EST/SULT1E1 expression may have a broader significance in the understanding of breast cancer prevention and treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES014626-05
Application #
7993558
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Reinlib, Leslie J
Project Start
2006-12-01
Project End
2012-11-30
Budget Start
2010-12-01
Budget End
2012-11-30
Support Year
5
Fiscal Year
2011
Total Cost
$340,197
Indirect Cost
Name
University of Pittsburgh
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
He, Jinhan; Hu, Bingfang; Shi, Xiongjie et al. (2013) Activation of the aryl hydrocarbon receptor sensitizes mice to nonalcoholic steatohepatitis by deactivating mitochondrial sirtuin deacetylase Sirt3. Mol Cell Biol 33:2047-55
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
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; Xie, Wen (2012) Targeting xenobiotic receptors PXR and CAR for metabolic diseases. Trends Pharmacol Sci 33:552-8
He, Jinhan; Lee, Jung Hoon; Febbraio, Maria et al. (2011) The emerging roles of fatty acid translocase/CD36 and the aryl hydrocarbon receptor in fatty liver disease. Exp Biol Med (Maywood) 236:1116-21
Ou, Zhimin; Wada, Taira; Gramignoli, Roberto et al. (2011) MicroRNA hsa-miR-613 targets the human LXRα gene and mediates a feedback loop of LXRα autoregulation. Mol Endocrinol 25:584-96
Wada, Taira; Ihunnah, Chibueze A; Gao, Jie et al. (2011) Estrogen sulfotransferase inhibits adipocyte differentiation. Mol Endocrinol 25:1612-23
Ihunnah, Chibueze A; Jiang, Mengxi; Xie, Wen (2011) Nuclear receptor PXR, transcriptional circuits and metabolic relevance. Biochim Biophys Acta 1812:956-63
He, Jinhan; Nishida, Shigeru; Xu, Meishu et al. (2011) PXR prevents cholesterol gallstone disease by regulating biosynthesis and transport of bile salts. Gastroenterology 140:2095-106
He, Jinhan; Cheng, Qiuqiong; Xie, Wen (2010) Minireview: Nuclear receptor-controlled steroid hormone synthesis and metabolism. Mol Endocrinol 24:11-21

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