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

• 批准号: 8445401
• 负责人: David Yiu-Kwan Hui
• 金额: $ 28.03万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 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/8445401
• 关键词: Adipocytes; Adipose tissue; Adverse effects; Alzheimer' 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

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）：遗传关联研究已经确定LDL受体相关蛋白-1（LRP 1）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，其充当许多不同配体的货物转运内吞受体以及在调节细胞功能中具有细胞信号传导性质的受体。在过去的资助期间获得的结果表明，脂肪细胞中的LRP 1失活产生了对饮食诱导的肥胖和糖尿病有抵抗力的动物。然而，LRP 1缺陷型脂肪细胞功能失调，炎症基因表达升高。我们的研究结果还表明，肝脏特异性LRP 1失活减少HDL的产生，降低血浆HDL-胆固醇水平，并促进损伤诱导的脂肪性肝炎和肝硬化。综上所述，这些结果表明，LRP 1在脂肪和肝脏中的失活促进了其他代谢紊乱，尽管它可以防止饮食诱导的肥胖和糖尿病。最新数据显示，LRP 1失活减少了脂肪细胞和肝细胞中的溶酶体酶加工。该项目的目标是测试LRP 1抑制饮食诱导的组织功能障碍和炎症，并通过调节溶酶体酶分选和受体细胞信号传导事件防止损伤诱导的脂肪性肝炎的总体假设。具体目标1将描述LRP 1缺乏抑制脂肪细胞分化和促进脂肪功能障碍和炎症的机制，测试组成型PDGF受体活化沿着溶酶体酶加工缺陷和LRP 1缺乏导致的自噬受损是这些代谢异常的原因的假设。具体目标2将测试脂肪细胞LRP 1缺陷加剧血管闭塞性疾病的假设，包括饮食诱导的动脉粥样硬化和损伤诱导的新生内膜增生，尽管它对饮食诱导的肥胖和糖尿病有保护作用。具体目标3将检验以下假设：在肝LRP 1缺乏的情况下观察到的HDL分泌减少和损伤诱导的肝脂肪性肝炎增加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减少所致。综上所述，这些研究将阐明脂肪和肝脏特异性LRP 1失活的有益作用与不良作用，以便为代谢和心血管风险管理提供合理的治疗建议。