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

描述(申请人提供)：遗传关联研究已经确认低密度脂蛋白受体相关蛋白-1(LRP1)的多态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，作为许多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特性的受体。在过去的资助期间获得的结果显示，脂肪细胞中LRP1的失活产生了对饮食诱导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，炎性基因表达增加。我们的结果还表明，肝脏特异性失活的LRP1减少了高密度脂蛋白的产生，降低了血浆高密度脂蛋白-胆固醇水平，并促进了损伤诱导的脂肪性肝炎和肝硬变。综上所述，这些结果表明，LRP1在脂肪和肝脏中的失活会促进其他代谢紊乱，尽管它可以预防饮食诱导的肥胖和糖尿病。最新数据显示，LRP1失活会减少脂肪细胞和肝细胞中溶酶体酶的处理。该项目的目标是验证LRP1通过调节溶酶体酶分类和受体细胞信号事件来抑制饮食诱导的组织功能障碍和炎症以及预防损伤诱导的脂肪性肝炎的总体假设。具体目标1将阐明LRP1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，验证结构性PDGF受体激活、溶酶体酶加工缺陷和LRP1缺乏导致的自噬功能受损导致这些代谢异常的假说。具体目标2将检验这样一个假设，即脂肪细胞LRP1缺乏会加剧血管闭塞疾病，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，尽管它可以预防饮食诱导的肥胖和糖尿病。具体目标3将测试假设，即肝脏LRP1缺陷所观察到的损伤性脂肪性肝炎的高密度脂蛋白分泌减少和增加是由于溶酶体酶加工和自噬和/或蛋白酶-蛋白酶抑制物复合体清除减少所致。综上所述，这些研究将阐明脂肪和肝脏特异性LRP1失活的益处和不利影响，以便为代谢和心血管风险管理提供合理的治疗建议。 公共卫生相关性：遗传关联研究已确定低密度脂蛋白受体相关蛋白-1(LRP1)的多态是代谢和心血管疾病的风险因素。这项建议将描述脂肪和肝脏中LRP1活性调节代谢性疾病风险的机制(S)。这项基于机制的研究的临床意义在于，在对代谢和心血管风险管理提出任何治疗建议之前，有必要澄清脂肪和肝脏LRP1的有益和不利影响。

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.