HEPATIC CLEARANCE OF APOLIPOPROTEIN B

载脂蛋白 B 的肝脏清除率

• 批准号: 3340890
• 负责人: CHARLES Edward SPARKS
• 金额: $ 20.01万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-04-01 至 1989-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3340890
• 关键词: affinity chromatography; apolipoproteins; blood lipoprotein biosynthesis; blood lipoprotein metabolism; chemical structure function; cholesterol esters; conformation; gel electrophoresis; gel filtration chromatography; immunochemistry; isolation perfusion; lipase; lipoprotein lipase; liver metabolism; monoclonal antibody; radiotracer; tissue /cell culture; triglycerides

Apo B variant composition of triglyceride-rich lipoproteins (TRL) has an influence on the catabolic fate of the lipoprotein (Lp) particle. Although differences in apo BH (higher Mr apo B) and apo BL (lower Mr apo B) metabolism have been reported, reasons for the heterogeneity remain to be explored. Receptor-mediated Lp removal has been studied extensively and recent evidence suggests that apo BL does not interact with the chylomicron (CM) remnant receptor pathway in the liver. Thus, reasons for heterogenous apo B metabolism probably occur prior to receptor events and are a property of particles. Rats, in contrast to rabbits and humans, have both apo B variants in hepatically synthesized TRL. TRL modification by lipases (lipoprotein lipase and/or hepatic lipase) is necessary before preferential hepatic apo BL clearance is observed. Other factors which determine Lp clearance include apo C composition, apo CIII:CII ratio, apo E content, triglyceride vs. cholesterol ester content, physical size, and metabolic state. What is not known is how these events alter Lp structure in a way as to affect the subsequent catabolic fate of the Lp. The hypothesis to be tested is that observed heterogeneous metabolism of apo B-containing Lps relates to apo B expression which in turn is influenced by particle lipid and apoprotein composition. Study of hepatic clearance of Lp apo B is proposed stressing pre-receptor events (synthetic and lipolytic) which alter Lp composition. Favorable apoprotein composition for hepatic clearance of Lps will be determined and will be related to hepatic clearance pathways. We have developed monoclonal antibodies (mAbs) to rat apoproteins which will be used to isolate subpopulations of Lps of unique epitope composition for catabolic studies. Other mAbs will also be used in sensitive immunoassays for conformational epitopes present on Lps to allow development of two site assays in order to determine other apo B epitopes and apoprotein epitopes present on particles. Proposed experiments will continue studies of apo B turnover in vivo and in liver perfusion. Models of altered metabolic circumstances will include the streptozotocin diabetic, PAN-nephrotic and cholesterol-fed rat and we will extend catabolic studies to primary rat and rabbit hepatocyte cultures. Particle composition of apo B Lps is seen as critical to hepatic clearance. Studies assume importance considering the relationship of apo B-Lps as positive risk factors in atherogenesis.

富含甘油三酯的脂蛋白（TRL）的Apo B变体组合物具有 对脂蛋白（Lp）颗粒分解代谢命运的影响。 虽然 载脂蛋白BH（载脂蛋白B先生较高）和载脂蛋白BL（载脂蛋白B先生较低）的差异 代谢的报道，异质性的原因仍然是 探讨了 受体介导的脂蛋白清除已被广泛研究， 最近的证据表明，载脂蛋白BL不与乳糜微粒相互作用， (CM)肝脏中的残余受体途径。 因此，异质性的原因 载脂蛋白B代谢可能发生在受体事件之前， 的粒子。 与兔子和人类相比，大鼠既有载脂蛋白B， 肝脏合成TRL的变体。 脂肪酶对TRL的修饰 （脂蛋白脂肪酶和/或肝脂肪酶）是必要的， 观察到肝载脂蛋白BL清除。 决定Lp的其他因素 清除率包括载脂蛋白C组成、载脂蛋白CIII：CII比例、载脂蛋白E含量， 甘油三酯与胆固醇酯含量、身体大小和代谢 状态 目前尚不清楚的是，这些事件如何以某种方式改变Lp结构 从而影响Lp的后续分解代谢命运。 假设是 检测的是观察到的含载脂蛋白B的脂蛋白的异质代谢， 与apo B表达相关，而apo B表达又受颗粒脂质的影响 和脱辅基蛋白组成。 脂蛋白apo B is肝清除率的研究 建议强调受体前事件（合成和脂解）， 改变Lp组成。 肝脏的有利载脂蛋白组成 将确定LPS的清除率，并将与肝脏相关 清除路径。 我们已经开发了抗大鼠的单克隆抗体（mAb）， 载脂蛋白，将用于分离独特的脂蛋白亚群， 表位组合物用于分解代谢研究。 其他mAb也将用于 对LPS上存在的构象表位进行灵敏的免疫测定， 开发双位点测定法，以确定其他载脂蛋白B表位 和存在于颗粒上的脱辅基蛋白表位。 拟议的实验将 继续研究载脂蛋白B在体内和肝脏灌注中的转换。 模型 包括链脲佐菌素 糖尿病，PAN肾病和胆固醇喂养大鼠，我们将延长 原代大鼠和兔肝细胞培养物的分解代谢研究。 颗粒 载脂蛋白B脂蛋白的组成被认为是肝清除的关键。 研究 考虑到载脂蛋白B-Lps的关系为阳性，认为其重要性 动脉粥样硬化形成的危险因素。