The role of hepatic Sortlin 1 in diabetic dyslipidemia

描述(由申请人提供)：我们研究的长期目标是提高对脂代谢复杂调节的了解，并确定治疗糖尿病血脂异常的潜在靶点。糖尿病血脂异常的特征是血浆甘油三酯升高，高密度脂蛋白(HDL)降低，低密度脂蛋白(LDL)通常较小和致密。这种致动脉粥样硬化性脂质显著增加心血管疾病(CVD)的风险，心血管疾病约占糖尿病总死亡率的75%，这突显了有效控制糖尿病患者血脂异常的必要性。高甘油三酯血症是心血管疾病的独立危险因素。这个项目的目标是定义肝脏的新角色 山梨素1(Sort1)对肥胖和糖尿病患者血浆甘油三酯代谢的调节。Sort1是一种跨膜受体，在各种生物过程中调节细胞蛋白质的运输、分泌或降解。导致这项拟议研究的关键发现是，最近的全基因组关联分析发现，在大量人类群体中，SORT1基因与血浆低密度脂蛋白胆固醇、甘油三酯和心血管疾病风险之间存在非常强且可重复的关联，并且肝脏Sort1水平的增加导致小鼠血浆脂质的显著降低。然而，肝脏Sort1调节血脂的机制尚不完全清楚。此外，目前对肝脏Sort1是如何调控的还缺乏了解。鉴于该领域的知识差距，这项拟议的研究旨在解决两个问题：第一，肝脏索尔特1如何降低血浆甘油三酯？第二，肥胖和糖尿病患者肝脏Sort1显著降低的原因是什么？这项研究将通过检验以下中心假设来解决这些问题：肝脏Sort1与ApoA5相互作用并促进ApoA5的分泌，ApoA5激活脂蛋白脂酶刺激血浆TG清除，从而降低血浆TG。在肥胖和糖尿病中，炎症信号的慢性激活和胰岛素信号的受损可能通过促进翻译后蛋白降解而降低肝脏Sort1，而肝脏Sort1的减少可能参与肥胖和糖尿病高甘油三酯血症的发生和发展。具体目标1将使用肝脏特异的Sort1功能获得和功能丧失的小鼠模型来确定肝脏Sort1调节血浆甘油三酯代谢的效果和机制。具体目标2将描述肥胖和糖尿病患者肝脏Sort1基因翻译后下调的分子机制。具体地说，这个目标将调查炎症和胰岛素抵抗如何通过改变Sort1翻译后修饰、细胞运输过程和蛋白质稳定性来损害肝脏Sort1的功能。预计这项研究将提供新的机制洞察 人类肝脏Sort1与血脂之间的强烈联系，以及肝脏Sort1在糖尿病血脂异常的发病机制和治疗中的潜在新意义。

DESCRIPTION (provided by applicant): The long-term goal of our research is to improve the understanding of the complex regulation of lipid metabolism and to identify potential targets for the treatment of diabetic dyslipidemia. Diabetic dyslipidemia is characterized by elevated plasma triglyceride, reduced high-density lipoprotein (HDL) and often smaller and denser low-density lipoprotein (LDL). Such atherogenic lipid profile significantly increases the risk of cardiovascular disease (CVD), which accounts for ~75% of all mortality in diabetes, underscoring the need to effectively manage dyslipidemia in diabetes. Hypertriglyceridemia is an independent risk factor for CVD. The goal of this project is to define the novel role of hepatic Sortilin 1 (Sort1) in the regulation of plasma triglyceride metabolism in obesity and diabetes. Sort1 is a trans-membrane receptor that regulates the transport, secretion or degradation of cellular proteins in various biological processes. The key discovery that has led to this proposed research is that recent genome-wide association analyses identified very strong and reproducible association of SORT1 gene with plasma LDL cholesterol, triglyceride and CVD risk in large human populations, and that increasing hepatic Sort1 levels caused marked reduction of plasma lipids in mice. However, the mechanisms by which hepatic Sort1 regulates plasma lipids is not fully clear. In addition, current knowledge on how hepatic Sort1 is regulated is stil lacking. Given such knowledge gaps in the field, this proposed study aims to address two questions: First, how does liver Sort1 lower plasma triglyceride? Second, what causes significantly reduced hepatic Sort1 in obesity and diabetes? This study will address these questions by testing the following central hypothesis: Hepatic Sort1 interacts with and promotes the secretion of ApoA5, which activates lipoprotein lipase to stimulate plasma TG clearance and thus lowers plasma TG. In obesity and diabetes, chronic activation of inflammatory signaling and impaired insulin signaling reduce hepatic Sort1 via promoting posttranslational protein degradation, and decreased hepatic Sort1 may contribute to the development and progression of hypertriglyceridemia in obesity and diabetes. Specific aim 1 will use liver-specific Sort1 gain-of-function and loss-of-function mouse models to define the effects and mechanisms of hepatic Sort1 regulation of plasma triglyceride metabolism. Specific aim 2 will delineate the molecular mechanisms of posttranslational down-regulation of liver Sort1 in obesity and diabetes. Specifically, this aim will investigate how inflammation and insulin resistance impair hepatic Sort1 function by altering Sort1 posttranslational modifications, cellular transport process and protein stability. It is expected that this research will provide new mechanistic insights into the strong link between hepatic Sort1 and plasma lipids in humans, and the potential new implications of hepatic Sort1 in the pathogenesis and treatment of diabetic dyslipidemia.