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.
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