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

描述(由申请人提供)： 代谢综合征影响着美国超过25%的成年人，与心血管疾病和血脂异常有关，包括血清甘油三酯升高和高密度脂蛋白(HDL)水平降低。高密度脂蛋白通过促进体内多余胆固醇的排出和携带防止炎症的蛋白质来预防动脉粥样硬化。 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抵抗力，而其他分支仍然敏感。叠加在这些变化之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导致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。 这项应用的具体目标是确定胰岛素信号通路的不同分支如何控制高密度脂蛋白和固醇调节元件结合蛋白(SREBP)-1c，后者是一种调节血清甘油三酯的核转录因子。中心假说是，Akt下游的胰岛素抵抗导致高密度脂蛋白的前动脉粥样硬化改变，而激活SREBP-1c需要胰岛素信号级联其他分支的持续敏感性。为了验证这一假说，我们将(1)通过使肝脏胰岛素信号缺陷的小鼠接受高脂喂养，确定是否有必要通过胰岛素受体激活代谢综合征中的SREBP-1c；(2)通过测量所有肝脏胰岛素信号缺陷的小鼠和通过Akt检测高密度脂蛋白代谢相关酶的清除情况以及参与高密度脂蛋白代谢的酶的表达，确定调节高密度脂蛋白的胰岛素信号分支；以及(3)利用质谱学方法确定肝脏胰岛素抵抗是否降低了与高密度脂蛋白相关的动脉粥样硬化保护蛋白。这些研究将确定逆转代谢综合征血脂异常的迫切需要的靶点。

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.