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质代谢复杂调节的理解，并确定治疗糖尿病血脂异常的潜在靶点。糖尿病性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）通常更小更密。这种致动脉粥样硬化的脂质谱显著增加了心血管疾病（CVD）的风险，心血管疾病占糖尿病所有死亡率的约75%，强调了有效管理糖尿病血脂异常的必要性。高胆固醇血症是CVD的独立危险因素。该项目的目标是确定肝脏的新作用， Sortilin 1（Sort 1）对肥胖和糖尿病患者血浆甘油三酯代谢的调节作用Sort 1是一种跨膜受体，在各种生物过程中调节细胞蛋白质的转运、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确定了SORT 1基因与大量人群中血浆LDL胆固醇，甘油三酯和CVD风险的非常强和可重复的关联，并且增加肝脏Sort 1水平导致小鼠血浆脂质显着降低。然而，肝脏Sort 1调节血脂的机制尚不完全清楚。此外，目前关于肝脏Sort 1如何调节的知识仍然缺乏。鉴于该领域的知识空白，这项拟议的研究旨在解决两个问题：第一，肝脏Sort 1如何降低血浆甘油三酯？二、是什么原因导致肥胖和糖尿病患者肝脏Sort1显著降低？本研究将通过检验以下中心假设来解决这些问题：Hepatic Sort 1与ApoA5相互作用并促进ApoA5的分泌，ApoA5激活脂蛋白脂肪酶以刺激血浆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受损的胰岛素信号通过促进翻译后蛋白降解降低肝脏Sort 1，并且肝脏Sort 1的降低可能有助于肥胖和糖尿病中高甘油三酯血症的发生和进展。具体目标1将使用肝脏特异性Sort 1功能获得和功能丧失小鼠模型来确定肝脏Sort 1调节血浆甘油三酯代谢的作用和机制。具体目标2将描述肥胖和糖尿病中肝脏Sort 1翻译后下调的分子机制。具体而言，本研究将探讨炎症和胰岛素抵抗如何通过改变Sort 1的翻译后修饰、细胞转运过程和蛋白质稳定性来损害肝脏Sort 1的功能。预计这项研究将提供新的机制的见解， 人类肝脏Sort 1与血脂之间的密切联系，以及肝脏Sort 1在糖尿病血脂异常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.