The role of hepatic Sortlin 1 in diabetic dyslipidemia

肝 Sortlin 1 在糖尿病血脂异常中的作用

• 批准号: 9262921
• 负责人: Tiangang Li
• 金额: $ 32.84万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-10 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9262921
• 关键词: 1p13; APOA5 gene; Address; Adipose tissue; Affect; Biological Process; Cardiovascular Diseases; Carrier Proteins; Cholesterol; Chronic; Complex; Coronary Arteriosclerosis; Development; Diabetes Mellitus; Diabetic mouse; Down-Regulation; Dyslipidemias; Fatty Acids; Functional disorder; Genes; Genetic Variation; Goals; Golgi Apparatus; Health; Hepatic; Hepatocyte; High Density Lipoproteins; Homeostasis; Human; Hypertriglyceridemia; Impairment; Inflammation; Inflammatory; Insulin Resistance; Knowledge; LDL Cholesterol Lipoproteins; Ligands; Link; Lipids; Liver; Low-Density Lipoproteins; MAP Kinase Gene; Molecular; Morbidity - disease rate; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Pathogenesis; Pathologic; Pattern; Phosphorylation; Plasma; Play; Population; Post-Translational Protein Processing; Prevention; Proteins; Regulation; Reporting; Reproducibility; Research; Role; Signal Transduction; Testing; Transport Process; Triglyceride Metabolism; Triglycerides; base; cardiovascular disorder risk; cardiovascular risk factor; diabetic; diabetic patient; disorder risk; gain of function; genome wide association study; improved; insight; insulin signaling; knock-down; lipid metabolism; lipoprotein lipase; loss of function; mortality; mouse model; novel; overexpression; protein degradation; protein transport; public health relevance; receptor; sortilin; trafficking; uptake

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.

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标。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）降低以及通常更小且密度更高的低密度脂蛋白（LDL）。这种致动脉粥样硬化的血脂状况显着增加了心血管疾病 (CVD) 的风险，心血管疾病约占糖尿病死亡率的 75%，这凸显了有效管理糖尿病血脂异常的必要性。高甘油三酯血症是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 (Sort1) 在肥胖和糖尿病中调节血浆甘油三酯代谢。 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。促成这项研究的关键发现是，最近的全基因组关联分析发现，SORT1 基因与大量人群中的血浆 LDL 胆固醇、甘油三酯和 CVD 风险具有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显着降低。然而，肝脏 Sort1 调节血脂的机制尚不完全清楚。此外，目前关于肝脏 Sort1 如何调节的知识仍然缺乏。鉴于该领域的知识差距，本研究旨在解决两个问题：首先，肝脏 Sort1 如何降低血浆甘油三酯？其次，肥胖和糖尿病患者肝脏Sort1显着降低的原因是什么？本研究将通过测试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胰岛素信号受损会通过促进翻译后蛋白降解来减少肝脏 Sort1，而肝脏 Sort1 的减少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Sort1功能获得和功能丧失小鼠模型来确定肝脏Sort1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 Sort1 翻译后下调的分子机制。具体来说，该目标将研究炎症和胰岛素抵抗如何通过改变 Sort1 翻译后修饰、细胞转运过程和蛋白质稳定性来损害肝脏 Sort1 功能。预计这项研究将提供新的机制见解 肝脏 Sort1 与人类血浆脂质之间的密切联系，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影响。