Sulfotransferase Expression: Implications for Toxicity

描述（由申请方提供）：作为人肝脏中的主要解毒酶，羟基类固醇磺基转移酶（SULT 2A）催化生物学上重要的内源性和外源性底物（包括激素、胆固醇中间体、药物和前致癌物）的磺化。磺化甾醇代谢产物正在成为调节肝脏核受体活性的新候选物。我们以前证明，SULT 2A转录是由人类和啮齿动物肝脏中的脂质敏感核受体调节的。最近，发现肾硫酸盐转运蛋白表达无效的低硫酸盐血症小鼠发生肝脏脂质和胆固醇代谢改变，沿着选择性诱导肝脏SULT 2A表达。这些结果表明硫酸盐稳态作为代谢疾病的一个未充分研究的方面的作用。我们的假设是肝脏SULT 2A 1是肝脏X受体（LXR）信号传导的环境敏感决定因素。SULT 2A 1催化内源性固醇的磺化，从而调节LXR靶基因的表达，包括SULT 2A 1本身。SULT 2A 1转录受以下两种机制调节：（1）外源性敏感受体，即二甲双胍X受体（PXR），通过与肝细胞核因子41（HNF 41）的相互作用;（2）在硫酸盐耗竭条件下，通过上述LXR介导的自身调节机制。拟议研究的具体目标是：（1）确定HNF 41和PXR在利福平调节人肝SULT 2A 1转录中的作用，（2）确定介导SULT 2A响应于低硫酸盐血症上调的机制，（3）鉴定代表SULT 2A 1生理底物的内源性肝甾醇，和（4）确定磺化甾醇的能力，相对于其未磺化的对应物，作为人LXR活性的调节剂起作用。总的来说，这项工作的影响，在人类的胆固醇和硫酸盐代谢的代谢紊乱，并将提供新的见解的相互作用的核受体和内源性中间体作为调节剂的外源性解毒和代谢在人类肝脏。公共卫生相关性：项目叙述性动脉粥样硬化被恰当地称为“心脏肝病”（Davis和Hui，2004）。肝脏脂质代谢的环境调节剂，有利于胰岛素抵抗性糖尿病和冠状动脉疾病的发生是目前未知的。然而，一个主要的候选人是“胆固醇磺基转移酶”（SULT 2A 1），一种药物和脂肪代谢酶在人类肝脏中，我们假设发挥了重要作用，在控制的基本脂质代谢途径，导致心脏病。这项拟议中的研究将为人类肝脏中胆固醇代谢的环境敏感成分提供新的线索，这些成分是人类糖尿病，肝脏和心脏病的前奏。

DESCRIPTION (provided by applicant): As a major detoxicating enzyme in human liver, hydroxysteroid sulfotransferase (SULT2A) catalyzes the sulfonation of biologically important endogenous and xenobiotic substrates, including hormones, cholesterol intermediates, pharmaceuticals and procarcinogens. Sulfonated sterol metabolites are emerging as novel candidates for the modulation of nuclear receptor activity in the liver. We previously demonstrated that SULT2A transcription is regulated by lipid-sensing nuclear receptors in human and rodent liver. Recently, hyposulfatemic mice with nullified expression of a renal sulfate transporter were found to develop altered hepatic lipid and cholesterol metabolism along with selectively induced expression of hepatic SULT2A. These results suggest a role for sulfate homeostasis as an under-studied facet of metabolic disease. Our hypothesis is that hepatic SULT2A1 is an environmentally-sensitive determinant of liver X receptor (LXR) signaling. SULT2A1 catalyzes the sulfonation of endogenous sterols, thereby modulating the expression of LXR target genes, including SULT2A1 itself. SULT2A1 transcription is regulated (1) by the xenobiotic-sensing receptor, pregnane X receptor (PXR), through interactions involving hepatocyte nuclear factor 41 (HNF41) and (2) under conditions of sulfate depletion, through the above-described LXR-mediated autoregulatory mechanism. The specific aims of the proposed research are to: (1) Define the roles of HNF41 and PXR in the modulation of human hepatic SULT2A1 transcription by rifampicin, (2) Define the mechanism mediating SULT2A up-regulation in response to hyposulfatemia, (3) Identify endogenous hepatic sterols that represent physiological substrates for SULT2A1, and (4) Determine the abilities of sulfonated sterols, relative to their unsulfonated counterparts, to function as modulators of human LXR activity. Overall, this work has implications for metabolic disturbances in cholesterol and sulfate metabolism in humans, and will provide new insights into the interactive roles of nuclear receptors and endogenous intermediates as modulators of xenobiotic detoxication and metabolism in human liver. PUBLIC HEALTH RELEVANCE: Project Narrative Atherosclerosis has been aptly called a "liver disease of the heart" (Davis and Hui, 2004). The environmental modifiers of hepatic lipid metabolism that favor the genesis of insulin resistant diabetes and coronary artery disease are presently unknown. However, a prime candidate is "cholesterol sulfotransferase" (SULT2A1), a drug- and hormone-metabolizing enzyme in human liver that we hypothesize plays a major role in the control of the essential lipid metabolism pathways leading to heart disease. The proposed research will shed new light on the environmentally-sensitive components of cholesterol metabolism in human liver that serve as a prelude to diabetes, liver and heart disease in humans.