MOLECULAR REGULATION OF APOPROTEIN B DEGRADATION

描述(摘自申请者的摘要)：冠心病的风险 动脉疾病(CAD)与血浆血管紧张素Ⅱ水平呈正相关 载脂蛋白B(ApoB)。载脂蛋白B是脂蛋白的主要蛋白质成分 运送大量胆固醇和甘油三酯的颗粒 肝到外周组织，如动脉壁。详细知识 因此，对肝脏载脂蛋白B产生的调节具有很高的相关性 动脉粥样硬化是老年人死亡和发病的主要原因 美国人口。与大多数分泌蛋白不同，肝脏载脂蛋白B 生产不是由它的合成速度控制的，而是由它的数量控制的 新合成的载脂蛋白B及其转移的机制 降解的分泌途径尚不清楚。为了解决这些问题， 标准的人肝脂蛋白代谢体外模型--HepG2 细胞系，已有研究。脂肪酸缺乏的HepG2细胞表现出 内质网相关的载脂蛋白B降解(ERAD)，其中 新生多肽穿过内质网只是部分的，导致暴露 ApoB结构域结合到胞浆中。结果清楚地表明， 胞液结构，蛋白酶体，在脂肪酸缺乏时降解载脂蛋白B HepG2细胞。此外，蛋白酶体的降解还涉及到另一个 胞浆成分，伴侣Hsp70，已知在 以细胞蛋白质为靶标进行降解。使用单元格中的方法 和分子生物学，以及生物物理学，这些新的结果将 以确定载脂蛋白B的移位和降解机制 以及控制这些过程的因素。调查人员希望 最终开发新的策略来减少肝脏载脂蛋白B的产生和 从而降低CAD的风险。

DESCRIPTION (Adapted from applicant's abstract): The risk of coronary artery disease (CAD) is positively correlated with the plasma levels of apoprotein B (apoB). ApoB is the major protein component of the lipoprotein particles transporting the bulk of cholesterol and triglycerides from the liver to peripheral tissues, such as the arterial wall. Detailed knowledge of the regulation of hepatic apoB production, therefore, is highly relevant to atherosclerosis, a leading cause of mortality and morbidity in the American population. In contrast to most secretory proteins, hepatic apoB production is controlled not by its rate of synthesis, but by the amount of newly synthesized apoB and the mechanism by which apoB is diverted from the secretory pathway to degradation are not known. To address these issues, the standard in vitro model of human liver lipoprotein metabolism, the HepG2 cell line, has been studies. Fatty acid-deprived HepG2 cells exhibit ER-associated degradation of apoB (ERAD), in which the translocation of the nascent polypeptide across the ER is only partial, resulting in the exposure of apoB domains to the cytosol. The results indicate clearly that the cytosolic structure, the proteasome, degrades apoB in fatty acid-deprived HepG2 cells. In addition, proteasomal degradation involves another cytosolic component, the chaperone Hsp70, which is known to function in the targeting of cellular proteins to degradation. Using approaches from cell and molecular biology, as well as from biophysics, these novel results will be extended to identify the mechanisms of apoB translocation and degradation and the factors regulating these processes. The investigators hope to ultimately develop new strategies to decrease hepatic apoB production and thereby lower the risk of CAD.