LDL Receptor Related Protein-1 in Metabolic and Cardiovascular Disease Modulation

LDL 受体相关蛋白 1 在代谢和心血管疾病调节中的作用

基本信息

批准号：
8610294
负责人：
David Yiu-Kwan Hui
金额：
$ 29.05万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8610294
关键词：
Adipocytes Adipose tissue Adverse effects Alzheimer&apos s Disease Animals Apolipoprotein E Area Assimilations Atherosclerosis Attenuated Autophagocytosis Blood Circulation Blood Vessels Cardiovascular Diseases Carrier Proteins Cations Cell physiology Cells Cholates Cholesterol Clinical Complex Data Defect Development Diabetes Mellitus Diet Disease Disease Progression Effectiveness Enzymes Event Functional disorder Funding Gene Expression Genetic Polymorphism Goals Hepatic Hepatocyte High Density Lipoprotein Cholesterol High Density Lipoproteins Hyperlipidemia Hyperplasia IGF Type 2 Receptor Inflammation Inflammatory Inflammatory Response Injury Knockout Mice LDL-Receptor Related Protein 1 Ligands Lipids Lipoproteins Liver Liver Cirrhosis Maintenance Mediating Metabolic Metabolic Diseases Modification Mus Neoplasm Metastasis Neurodegenerative Disorders Nutrient Obesity Peptide Hydrolases Plasma Plasminogen Activator Inhibitor 1 Platelet-Derived Growth Factor Receptor Play Process Production Property Protease Inhibitor Proteins Receptor Activation Receptor Cell Receptor Signaling Recommendation Regulation Resistance Risk Factors Risk Management Role Severities Signal Transduction Smooth Muscle Myocytes Sorting - Cell Movement Steatohepatitis Suggestion Testing Therapeutic Tissues Transplantation Tumor Cell Invasion Vascular Diseases adipocyte differentiation base cardiovascular risk factor chylomicron remnant disorder risk genetic association lipid transport macromolecule nutrient metabolism premature atherosclerosis public health relevance receptor receptor function response therapeutic target uptake

项目摘要

DESCRIPTION (provided by applicant): Genetic association studies have identified polymorphism of LDL receptor-related protein-1 (LRP1) as a risk factor for metabolic diseases including premature atherosclerosis. This is a multi- functional receptor that serves as a cargo transporting endocytic receptor for numerous different ligands as well as a receptor with cell signaling properties in modulating cell functions. Results obtained during the past funding period showed LRP1 inactivation in adipocytes yielded animals that are resistant to diet- induced obesity and diabetes. However, the LRP1-deficient adipocytes are dysfunctional with elevated inflammatory gene expression. Our result also showed that liver-specific inactivation of LRP1 reduces HDL production, lowers plasma HDL-cholesterol levels, and promotes injury-induced steatohepatitis and liver cirrhosis. Taken together, these results indicate that LRP1 inactivation in adipose and liver promotes other metabolic disorders despite its protection against diet induced-obesity and diabetes. The latest data revealed LRP1 inactivation reduces lysosomal enzyme processing in both adipocytes and hepatocytes. The goal of this project is to test the overall hypothesis that LRP1 suppresses diet-induced tissue dysfunctions and inflammation and protects against injury-induced steatohepatitis via modulation of lysosomal enzyme sorting and receptor cell signaling events. Specific Aim 1 will delineate the mechanism by which LRP1 deficiency inhibits adipocyte differentiation and promotes adipose dysfunction and inflammation, testing the hypothesis that constitutive PDGF receptor activation along with defective lysosomal enzyme processing and impaired autophagy due to LRP1 deficiency are responsible for these metabolic abnormalities. Specific Aim 2 will test the hypothesis that adipocyte LRP1 deficiency exacerbates vascular occlusive diseases, including diet-induced atherosclerosis and injury-induced neointimal hyperplasia, despite its protection against diet-induced obesity and diabetes. Specific Aim 3 will test the hypothesis that decreased HDL secretion and augmentation of injury-induced liver steatohepatitis observed with hepatic LRP1 deficiency are due to impaired lysosomal enzyme processing and autophagy and/or the reduced clearance of protease-protease inhibitor complexes. Taken together, these studies will clarify the beneficial versus adverse effects of adipose- and liver- specific LRP1 inactivation such that rational therapeutic recommendations can be made for metabolic and cardiovascular risk management.

描述（由申请人提供）：遗传关联研究确定了LDL受体相关蛋白-1（LRP1）的多态性是代谢性疾病（包括早产动脉粥样硬化）的危险因素。这是一种多功能受体，可作为许多不同不同配体的货物运输内吞受体，以及在调节细胞功能中具有细胞信号传导特性的受体。在过去的资金期间获得的结果表明，脂肪细胞中LRP1失活产生的动物对饮食诱发的肥胖症和糖尿病具有抗性。但是，LRP1缺陷型脂肪细胞功能障碍，炎症基因表达升高。我们的结果还表明，LRP1的肝脏特异性灭活可降低HDL的产生，降低血浆HDL-胆固醇水平，并促进损伤引起的脂肪性肝炎和肝硬化。综上所述，这些结果表明，尽管脂肪和肝脏中的LRP1灭活促进了其他代谢性疾病，尽管它保护了饮食诱发肥胖和糖尿病。最新数据显示，LRP1失活减少了脂肪细胞和肝细胞中的溶酶体酶加工。该项目的目的是测试LRP1抑制饮食引起的组织功能障碍和炎症的总体假设，并通过调节溶酶体酶分选和受体细胞信号传导事件来防止损伤诱导的脂肪性肝炎。具体目标1将描述LRP1缺乏抑制脂肪细胞分化并促进脂肪症功能障碍和炎症的机制，从而检验了一种假设，即组成型PDGF受体激活以及由于LRP1缺陷而导致的自动助剂构成了这些含量，因此质体酶处理有缺陷以及这些对LRP1的损害。具体目标2将检验以下假设：脂肪细胞LRP1缺乏加剧了血管闭塞性疾病，包括饮食引起的动脉粥样硬化和损伤引起的新内膜增生，尽管它可以保护饮食诱导的肥胖和糖尿病。具体的目标3将检验以下假设：肝LRP1缺乏观察到的HDL分泌减少和损伤诱导的肝脏脂肪性肝炎的增强是由于溶酶体酶加工和/或降低了蛋白酶蛋白酶促酶抑制剂复合物的清除率，这是由于溶酶体酶加工受损而引起的。综上所述，这些研究将阐明脂肪和肝脏特异性LRP1失活的有益与不利影响，从而可以对代谢和心血管风险管理提出合理的治疗建议。