The role of insulin signaling in the dyslipidemia of the metabolic syndrome

胰岛素信号在代谢综合征血脂异常中的作用

• 批准号: 7775101
• 负责人: Sudha B Biddinger
• 金额: $ 8.49万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7775101
• 关键词: 1-Phosphatidylinositol 3-Kinase; ADD-1 protein; Accounting; Adult; Affect; Antiatherogenic; Atherosclerosis; Binding Proteins; Cardiovascular Diseases; Cholesterol; Complex; Data; Diet; Dietary Factors; Disease; Dyslipidemias; Enzymes; Excision; Fatty acid glycerol esters; Figs - dietary; Goals; Grant; Hepatic; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Hypertriglyceridemia; Inflammation; Insulin; Insulin Receptor; Insulin Resistance; Insulin Signaling Pathway; Knockout Mice; Liver; Mass Spectrum Analysis; Measures; Mediating; Metabolic; Metabolic syndrome; Metabolism; Mus; Nuclear; Paper; Pathway interactions; Phosphatidylinositols; Phosphotransferases; Play; Protein Isoforms; Proteins; Proto-Oncogene Proteins c-akt; Publishing; Regulation; Regulatory Element; Resistance; Risk Factors; Role; Serum; Signal Transduction; Sterols; Sucrose; Testing; Triglycerides; United States; atheroprotective; base; feeding; insulin signaling; lipid biosynthesis; novel; prevent; transcription factor

DESCRIPTION (provided by applicant): The metabolic syndrome, which affects more than 25% of adults in the United States, is associated with cardiovascular disease and a dyslipidemia that includes increased serum triglycerides and low levels of high density lipoprotein (HDL). HDL protects against atherosclerosis by promoting the removal of excess cholesterol from the body, and by carrying proteins that protect against inflammation. The metabolic syndrome is a complex disorder in which some branches of the insulin signaling cascade become resistant to insulin, whereas others remain sensitive. Superimposed upon these changes are the direct effects of dietary factors. Dissecting the roles of the different branches of the insulin signaling pathway and dietary factors in producing dyslipidemia and atherosclerosis is an important step towards preventing cardiovascular disease. The specific goal of this application is to determine how the different branches of the insulin-signaling pathway control HDL and sterol regulatory element binding protein (SREBP)-1c, a nuclear transcription factor which regulates serum triglycerides. The central hypothesis is that insulin resistance downstream of Akt leads to pro-atherogenic changes in HDL, whereas continued sensitivity in other branches of the insulin signaling cascade is required for activation of SREBP-1c. To test this hypothesis, we will (1) determine whether signaling through the insulin receptor is necessary for activation of SREBP-1c in the metabolic syndrome by subjecting mice deficient in hepatic insulin signaling to high fat feeding; (2) determine the branch of insulin signaling that regulates HDL by measuring HDL clearance and expression of the enzymes involved in HDL metabolism in mice deficient in all hepatic insulin signaling and mice deficient only in hepatic signaling through Akt; and (3) determine whether hepatic insulin resistance decreases the atheroprotective proteins associated with HDL using mass spectroscopy. These studies will identify urgently needed targets for reversing the dyslipidemia of the metabolic syndrome.

描述（由申请人提供）： 代谢综合征影响美国超过25%的成年人，与心血管疾病和血脂异常相关，包括血清甘油三酯增加和高密度脂蛋白（HDL）水平降低。高密度脂蛋白通过促进从体内清除多余的胆固醇和携带蛋白质防止炎症来防止动脉粥样硬化。 代谢综合征是一种复杂的疾病，其中胰岛素信号级联的一些分支对胰岛素产生抗性，而其他分支仍然敏感。叠加在这些变化上的是饮食因素的直接影响。剖析胰岛素信号通路的不同分支和饮食因素在产生血脂异常和动脉粥样硬化中的作用是预防心血管疾病的重要一步。 本申请的具体目标是确定胰岛素信号传导途径的不同分支如何控制HDL和固醇调节元件结合蛋白（SREBP）-1c，这是一种调节血清甘油三酯的核转录因子。中心假设是Akt下游的胰岛素抵抗导致HDL的促动脉粥样硬化变化，而胰岛素信号级联的其他分支的持续敏感性是SREBP-1c激活所必需的。为了验证这一假设，我们将（1）通过对肝脏胰岛素信号传导缺陷的小鼠进行高脂肪喂养来确定通过胰岛素受体的信号传导是否是代谢综合征中SREBP-1c激活所必需的;（二）通过在所有肝胰岛素信号传导缺陷的小鼠中测量HDL清除率和参与HDL代谢的酶的表达来确定调节HDL的胰岛素信号传导的分支，和仅缺乏通过Akt的肝信号传导的小鼠;和（3）使用质谱确定肝胰岛素抵抗是否降低与HDL相关的动脉粥样硬化保护蛋白。这些研究将确定迫切需要的目标，扭转代谢综合征血脂异常。