The hepatic function of cholesterol sulfotransferase 2B1b (SULT2B1b)in energy met

胆固醇磺基转移酶2B1b（SULT2B1b）在能量代谢中的肝功能

• 批准号: 9087207
• 负责人: Wen Xie
• 金额: $ 33.5万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9087207
• 关键词: Acetate-CoA Ligase; Acetylation; Alkanesulfonates; Binding; Breeding; Cholesterol; Data; Down-Regulation; Eating; Energy Metabolism; Enzymes; Event; Exclusion; Fasting; Feedback; Gene Expression; Gene Targeting; Genes; Gluconeogenesis; Goals; Health; Hepatic; Hepatocyte; Homeostasis; Human; In Vitro; Insulin Resistance; Leptin; Liver; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Modeling; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Nuclear Translocation; Obese Mice; Obesity; Oxygen Consumption; Play; Production; Regulation; Role; SULT2B1; Testing; Therapeutic Agents; Transgenes; Transgenic Mice; Transgenic Organisms; Xenobiotics; base; cholesterol sulfotransferase; cholesteryl sulfate; feeding; glucose metabolism; improved; in vivo; insulin sensitivity; lipid metabolism; meetings; new therapeutic target; overexpression; promoter; sulfation; sulfotransferase

DESCRIPTION (provided by applicant): The cholesterol sulfotransferase SULT2B1b is a cytosolic sulfotransferase best known for its activity in sulfonating cholesterol and oxysterols. Metabolic syndrome, often manifested as obesity and insulin resistant type 2 diabetes, is a major health concern. The dysregulation of glucose and lipid metabolism plays an important pathogenic role in obesity and type 2 diabetes. Although the activity of SULT2B1b in catalyzing the sulfation of cholesterol has been documented, the role of SULT2B1b and its enzymatic byproduct cholesterol sulfate (CS) in energy metabolism and metabolic syndrome remains largely unknown. Our preliminary results showed that: 1) SULT2B1b was induced in obese mice and during the transition from the fasted to the fed state; 2) SULT2B1b and CS inhibited gluconeogenesis in hepatic cells; 3) SULT2B1b and CS specifically inhibited the gluconeogenic activity of HNF4α; 4) Treatment with CS inhibited gluconeogenesis and improved insulin sensitivity in both HFD and ob/ob models; 5) Transgenic overexpression of SULT2B1b improved metabolic functions in the HFD model; 6) Leptin is a potential effector for the metabolic benefit of SULT2B1b; 7) SULT2B1b and CS suppressed the expression of acetyl-coenzyme A synthetase 2 (Acss2), decreased the acetylation of HNF4α, and caused the nuclear exclusion of HNF4α; whereas a forced expression of Acss2 abolished the inhibitory effect of CS on HNF4α; 8) Down-regulation of HNF4α abolished the inhibitory effect of CS on gluconeogenesis in vitro; and 9) SULT2B1b is a potential HNF4α target gene, providing a possible mechanism of negative feedback regulation of gluconeogenesis. Based on our preliminary data, we hypothesize that the cholesterol sulfotransferase SULT2B1b has a previously unrecognized role in inhibiting gluconeogenesis and alleviating metabolic disease. Mechanistically, the metabolic benefit of SULT2B1b may have been achieved through its enzymatic byproduct cholesterol sulfate (CS) and by targeting the acetylation and nuclear translocation of the gluconeogenic transcriptional factor HNF4α. We also hypothesize that the SULT2B1 is a HNF4α target gene, which represents a negative feedback mechanism to limit the gluconeogenic activity of HNF4α. We anticipate that leptin is a potential effector of SULT2B1b in improving metabolic functions. By using the liver-specific SULT2B1b transgenic mice, in conjunction with HFD and ob/ob models of obesity and type 2 diabetes, we propose three Specific Aims to test our hypotheses: 1) To determine whether the liver-specific overexpression of SULT2B1b inhibits the ob/ob model of obesity and type 2 diabetes; 2) To determine the molecular mechanism by which SULT2B1b and CS inhibit gluconeogenesis; and 3) To determine whether the induction of SULT2B1b by HNF4α represents a potential mechanism of negative feedback regulation of gluconeogenesis. To our knowledge, this study represents the first attempt to comprehensively evaluate the endobiotic and hepatic function of SULT2B1b and its enzymatic byproduct CS in energy metabolism in vivo. Results from this study may establish SULT2B1b as a novel therapeutic target and CS as a therapeutic agent to manage metabolic disease.

描述（由申请方提供）：胆固醇磺基转移酶SULT 2B 1 b是一种胞质磺基转移酶，以其磺化胆固醇和氧固醇的活性而闻名。代谢综合征，通常表现为肥胖和胰岛素抵抗型2型糖尿病，是一个主要的健康问题。糖脂代谢紊乱在肥胖和2型糖尿病的发病中起重要作用。虽然SULT 2B 1b在催化胆固醇硫酸化中的活性已被证明，但SULT 2B 1b及其酶副产物胆固醇硫酸酯（CS）在能量代谢和代谢综合征中的作用仍不清楚。我们的初步研究结果表明：1）SULT 2B 1b在肥胖小鼠和从禁食到进食状态的过渡中被诱导; 2）SULT 2B 1b和CS抑制肝细胞的增生; 3）SULT 2B 1b和CS特异性地抑制HNF 4 α的增生活性; 4）CS治疗抑制HFD和ob/ob模型的增生并改善胰岛素敏感性; 5）SULT 2B 1b的过表达改善了HFD模型的代谢功能，6）Leptin是SULT 2B 1b代谢益处的潜在效应子，7）SULT 2B 1b和CS抑制乙酰辅酶A合成酶2（Acss 2）的表达，降低HNF 4 α的乙酰化，引起HNF 4 α的核排斥;而Acss 2的强制表达可消除CS对HNF 4 α的抑制作用; 8）HNF 4 α的下调可消除CS对体外胚胎发生的抑制作用; 9）SULT 2B 1b是HNF 4 α潜在的靶基因，可能是负反馈调节胚胎发生的机制。基于我们的初步数据，我们假设胆固醇磺基转移酶SULT 2B 1 b在抑制胆固醇生成和减轻代谢疾病方面具有以前未被认识到的作用。从机制上讲，SULT 2B 1b的代谢获益可能是通过其酶副产物胆固醇硫酸酯（CS）以及靶向致凋亡转录因子HNF 4 α的乙酰化和核转位实现的。我们还假设SULT 2B 1是HNF 4 α的靶基因，其代表了限制HNF 4 α致肿瘤活性的负反馈机制。我们预期瘦素是SULT 2B 1b改善代谢功能的潜在效应物。通过使用肝脏特异性SULT 2B 1 b转基因小鼠，结合肥胖和2型糖尿病的HFD和ob/ob模型，我们提出了三个具体目标来验证我们的假设：1）确定SULT 2B 1 b的肝脏特异性过表达是否抑制肥胖和2型糖尿病的ob/ob模型; 2）确定SULT 2B 1 b和CS抑制糖异生的分子机制;（3）探讨HNF 4 α对SULT 2B 1b的诱导作用是否是一种负反馈调控机制。据我们所知，这项研究代表了第一次尝试全面评估SULT 2B 1b及其酶副产物CS在体内能量代谢中的内源性和肝脏功能。这项研究的结果可能会建立SULT 2B 1b作为一种新的治疗靶点和CS作为一种治疗剂来管理代谢性疾病。