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：
8223148
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/8223148
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. PUBLIC HEALTH RELEVANCE: Genetic association studies have identified polymorphisms of the LDL receptor related protein-1 (LRP1) as a risk factor for metabolic and cardiovascular diseases. This proposal will delineate the mechanism(s) by which LRP1 activities in adipose and liver modulate metabolic disease risk. The clinical implication of this mechanism-based study is that clarification of the beneficial versus adverse effects of adipose- and liver-LRP1 is necessary before any therapeutic recommendations for metabolic and cardiovascular risk management can be made.

描述（由申请人提供）：遗传关联研究已确定 LDL 受体相关蛋白 1 (LRP1) 的多态性是包括过早动脉粥样硬化在内的代谢性疾病的危险因素。这是一种多功能受体，充当多种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。过去资助期间获得的结果表明，脂肪细胞中 LRP1 失活可产生对饮食引起的肥胖和糖尿病具有抵抗力的动物。然而，LRP1 缺陷的脂肪细胞功能失调，炎症基因表达升高。我们的结果还表明，LRP1 的肝脏特异性失活会减少 HDL 产生，降低血浆 HDL 胆固醇水平，并促进损伤诱发的脂肪性肝炎和肝硬化。总而言之，这些结果表明，脂肪和肝脏中的 LRP1 失活会促进其他代谢紊乱，尽管它可以预防饮食引起的肥胖和糖尿病。最新数据显示，LRP1 失活会减少脂肪细胞和肝细胞中的溶酶体酶加工。该项目的目标是检验以下总体假设：LRP1 通过调节溶酶体酶分选和受体细胞信号传导事件来抑制饮食引起的组织功能障碍和炎症，并预防损伤引起的脂肪性肝炎。具体目标 1 将描述 LRP1 缺乏抑制脂肪细胞分化并促进脂肪功能障碍和炎症的机制，检验以下假设：组成型 PDGF 受体激活以及溶酶体酶处理缺陷和 LRP1 缺乏导致的自噬受损是造成这些代谢异常的原因。具体目标 2 将检验脂肪细胞 LRP1 缺乏会加剧血管闭塞性疾病的假设，包括饮食引起的动脉粥样硬化和损伤引起的内膜增生，尽管它可以预防饮食引起的肥胖和糖尿病。具体目标 3 将检验以下假设：肝 LRP1 缺乏时观察到的 HDL 分泌减少和损伤诱发的肝脏脂肪性肝炎加重是由于溶酶体酶加工和自噬受损和/或蛋白酶-蛋白酶抑制剂复合物清除率降低所致。总而言之，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，以便为代谢和心血管风险管理提出合理的治疗建议。公共健康相关性：遗传关联研究已确定 LDL 受体相关蛋白 1 (LRP1) 的多态性是代谢和心血管疾病的危险因素。该提案将描述脂肪和肝脏中 LRP1 活性调节代谢疾病风险的机制。这项基于机制的研究的临床意义是，在提出代谢和心血管风险管理的任何治疗建议之前，有必要澄清脂肪和肝脏 LRP1 的有益与不利影响。