Sulfotransferase Expression: Implications for Toxicity
磺基转移酶表达:对毒性的影响
基本信息
- 批准号:7909169
- 负责人:
- 金额:$ 35.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-09-06 至 2013-08-31
- 项目状态:已结题
- 来源:
- 关键词:Alcohol sulfotransferaseAlkanesulfonatesAndrogensAromatic Polycyclic HydrocarbonsAtherosclerosisBile AcidsBiological AssayCholesterolCholesterol HomeostasisCoronary ArteriosclerosisDNA-Protein InteractionDiabetes MellitusEndocrine DisruptorsEnzymesExperimental ModelsGene ExpressionGene TargetingGenesGenetic TranscriptionHeartHeart DiseasesHepaticHepatocyteHigh Pressure Liquid ChromatographyHomeostasisHormonesHumanIn SituIn VitroInorganic SulfatesInsulin ResistanceInvestigationKidneyKineticsLigandsLightLipidsLiverLiver diseasesMass Spectrum AnalysisMediatingMediator of activation proteinMetabolicMetabolic DiseasesMetabolismMusNomenclatureNuclear ReceptorsParentsPathway interactionsPeroxisome Proliferator-Activated ReceptorsPharmaceutical PreparationsPharmacologic SubstancePhysiologicalPlayPositioning AttributePrimary Cell CulturesProcessProteinsRNA InterferenceRattusReceptor SignalingRecombinantsRegulationRelative (related person)ReporterResearchRifampinRodentRoleSterolsSteryl-sulfataseTestingToxic effectTransactivationTransfectionUnspecified or Sulfate Ion SulfatesUp-RegulationWorkXenobioticscholesterol sulfotransferasecholesteryl sulfatedehydroepiandrosteronedetoxicationhepatocyte nuclear factorinsightlipid metabolismmembermouse modelnovelpregnane X receptorpublic health relevancereceptorresearch studyresponsespecies differencesulfate transportersulfationsulfotransferase
项目摘要
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.
描述(申请人提供):作为人体肝脏中的一种主要解毒酶,羟基类固醇磺基转移酶(SULT2A)催化重要的内源性和外源性底物的磺化反应,包括激素、胆固醇中间体、药物和前致癌物。磺化的甾醇代谢物正在成为调节肝脏核受体活性的新候选物质。我们以前在人类和啮齿动物的肝脏中证明了SULT2A转录是由脂质感受性核受体调节的。最近,肾脏硫酸盐转运蛋白表达缺失的低硫血症小鼠被发现出现肝脏脂质和胆固醇代谢的改变,并选择性地诱导肝脏SULT2A的表达。这些结果表明硫酸盐动态平衡作为代谢性疾病的一个未被充分研究的方面的作用。我们的假设是,肝脏SULT2A1是肝脏X受体(LXR)信号的环境敏感决定因素。SULT2A1催化内源性甾醇的磺化,从而调节LXR靶基因的表达,包括SULT2A1本身。SULT2A1的转录是由异种生物感知受体孕烷X受体(PXR)通过涉及肝细胞核因子41(HNF41)的相互作用调节的,(2)在硫酸盐耗竭的条件下,通过上述LXR介导的自我调节机制。这项研究的具体目的是:(1)确定HNF41和PXR在利福平调节人肝SULT2A1转录中的作用;(2)确定SULT2A在低硫血症中上调的中介机制;(3)确定代表SULT2A1的生理底物的内源性肝脏甾醇;以及(4)确定磺化甾醇相对于其未磺化的类固醇作为人LXR活性调节器的能力。总体而言,这项工作对人类胆固醇和硫酸盐代谢的代谢紊乱具有意义,并将为核受体和内源性中间体作为异物解毒和代谢的调节器在人类肝脏中的相互作用提供新的见解。公共卫生相关性:项目叙述动脉粥样硬化被恰当地称为“心脏肝病”(Davis和Hui,2004)。促进胰岛素抵抗糖尿病和冠状动脉疾病发生的肝脂代谢环境调节剂目前尚不清楚。然而,首选候选基因是“胆固醇磺基转移酶”(SULT2A1),这是人类肝脏中的一种药物和激素代谢酶,我们推测它在控制导致心脏病的基本脂质代谢途径方面发挥着主要作用。这项拟议的研究将为人类肝脏中对环境敏感的胆固醇代谢成分提供新的线索,这些成分是人类糖尿病、肝脏和心脏病的前奏。
项目成果
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Melissa A Runge-Morris其他文献
Melissa A Runge-Morris的其他文献
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{{ truncateString('Melissa A Runge-Morris', 18)}}的其他基金
Expression, Regulation and Function of the SULT1C Carcinogen-Activating Enzymes
SULT1C 致癌物激活酶的表达、调节和功能
- 批准号:
10372105 - 财政年份:2014
- 资助金额:
$ 35.75万 - 项目类别:
Center For Urban Responses to Environmental Stressors (CURES)
城市环境压力应对中心 (CURES)
- 批准号:
9049259 - 财政年份:2014
- 资助金额:
$ 35.75万 - 项目类别:
Center For Urban Responses to Environmental Stressors (CURES)
城市环境压力应对中心 (CURES)
- 批准号:
8862474 - 财政年份:2014
- 资助金额:
$ 35.75万 - 项目类别:
Center for Urban Responses to Environmental Stressors (CURES)
城市环境压力应对中心 (CURES)
- 批准号:
9563390 - 财政年份:2014
- 资助金额:
$ 35.75万 - 项目类别:
Center for Urban Responses to Environmental Stressors (CURES)
城市环境压力应对中心 (CURES)
- 批准号:
9904628 - 财政年份:2014
- 资助金额:
$ 35.75万 - 项目类别:
Center For Urban Responses to Environmental Stressors (CURES)
城市环境压力应对中心 (CURES)
- 批准号:
8619364 - 财政年份:2014
- 资助金额:
$ 35.75万 - 项目类别:
Expression, Regulation and Function of the SULT1C Carcinogen-Activating Enzymes
SULT1C 致癌物激活酶的表达、调节和功能
- 批准号:
10570232 - 财政年份:2014
- 资助金额:
$ 35.75万 - 项目类别: