Regulation of Sulfotransferases by LXR and its Implication in Pathophysiology

LXR 对磺基转移酶的调节及其在病理生理学中的意义

• 批准号: 8075258
• 负责人: Wen Xie
• 金额: $ 2.87万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8075258
• 关键词: Agonist; Alcohol sulfotransferase; Bile Acids; Biological Assay; Biological Availability; Breast Cancer Prevention; Catabolism; Chemicals; Chemistry; Cholestasis; Cholesterol; DNA Binding; Development; Down-Regulation; Drug Metabolic Detoxication; Enzymes; Epithelial; Estrogen Receptors; Estrogens; Estrone sulfotransferase; Expressed Sequence Tags; Functional disorder; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genotype; Hepatocyte; Hepatotoxicity; Histology; Homeostasis; Homologous Gene; Hormones; Human; Individual; Inflammation; Knock-out; Lead; Ligands; Lipids; Lithocholic Acid; Liver; Luciferases; Mammary gland; Measures; Mediating; Modeling; Molecular; Mus; Pharmaceutical Preparations; Pharmacogenetics; Phase; Plasma; Play; Prevention; Protein Isoforms; Regulation; Reporter Genes; Research Personnel; Role; Testing; Time; Toxic effect; Transfection; Transgenic Mice; Transgenic Organisms; Wild Type Mouse; Xenobiotics; base; chromatin immunoprecipitation; gain of function; in vivo; lipid transport; liver function; loss of function; malignant breast neoplasm; novel; novel strategies; prevent; programs; promoter; receptor; response; sulfation; sulfotransferase; sulfotransferase SULT1E1; urinary

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.

肝脏X受体（LXR），包括a和p同种型，在肝脏中高度表达。LXR可以是 由内源性、天然和合成配体激活。以前对LXR的研究主要集中在它们的 在胆固醇和脂质稳态和炎症中的作用。然而，无论LXR是否在 调节外源性酶和转运蛋白，从而影响外源性和内源性 答案未知。我们的初步结果表明，表达激活的LXR α的转基因小鼠， （VP-LXRa）具有多种I相和II相酶以及可能的药物转运蛋白的改变的表达。 最值得注意的是VP-LXR小鼠和LXR小鼠中II期磺基转移酶（SULT）的诱导。 激动剂处理的野生型小鼠。这些包括SULT 2A 9，胆汁酸解毒羟基类固醇磺基转移酶， 和雌激素磺基转移酶（EST，或SULT 1 E1），其催化 雌激素。启动子分析强烈建议SULT 2A 9作为LXR的转录靶点。我们还展示 LXR α和β双敲除（LXR DKO）小鼠具有降低的SULT 2A 9基础表达。SULT 2A1， 在LXR激动剂处理的原代人肝细胞中诱导了SULT 2A 9的人同源物，表明 SULT 2A调节在人类中可能是保守的。EST/SULT 1 E1转基因小鼠的诱导 与抑制雌激素诱导的子宫上皮细胞增殖和雌激素受体靶点有关 基因表达。基于我们的初步结果，我们假设小鼠和/或人类SULT是 LXR的转录靶点。一个可检验的预测是，LXR介导的胆汁酸激活和 雌激素代谢SULT也可减轻胆汁酸肝毒性和胆汁淤积 体内雌激素活性下调。通过使用“功能获得性”VP-LXRa转基因，“功能丧失性”VP-LXRa转基因， 功能”LXR敲除和LXR配体处理的野生型小鼠，我们提出以下具体目标：（1） 确定LXRs的激活是否加剧胆汁酸肝毒性和胆汁淤积;（2）确定 LXRs的激活是否可以在功能上剥夺雌激素;和（3）通过以下方法确定分子基础： LXR调节小鼠和人SULT 2A和EST/SULT 1 E1。这些研究预计将 揭示了LXR在保护异种和内源性化学挑战中的新功能。我们建议LXR 通过增加胆固醇水平来维持胆固醇和胆汁酸的体内平衡 同时，防止胆汁酸积累的毒性。预计该 选择性LXR激动剂的开发可能代表了预防胆汁淤积和限制雌激素的新策略 体内活性。由于雌激素是乳腺癌的先决条件，描述LXR对乳腺癌的调节作用， EST/SULT 1 E1表达在乳腺癌的预防和治疗中可能具有更广泛的意义。 治疗