MOLECULAR REGULATION OF APOPROTEIN B DEGRADATION

脱辅蛋白 B 降解的分子调控

• 批准号: 6183872
• 负责人: Edward A Fisher
• 金额: $ 32.77万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-15 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6183872
• 关键词: apolipoproteins; blood lipoprotein metabolism; dietary lipid; dietary restriction; endoplasmic reticulum; fatty acids; hepatocellular carcinoma; intermolecular interaction; intracellular transport; molecular chaperones; nutrition related tag; proteasome; protein transport; tissue /cell culture; ubiquitin

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.

描述（改编自申请人摘要）：冠状动脉风险 动脉疾病（CAD）与血浆中 载脂蛋白B（apoB）。 载脂蛋白B是脂蛋白的主要蛋白质组分， 颗粒将大部分胆固醇和甘油三酯从 肝脏到外周组织，例如动脉壁。 详细知识 因此，肝脏apoB产生的调节是高度相关的， 动脉粥样硬化，一个主要的原因死亡率和发病率， 美国人口。 与大多数分泌蛋白不同，肝载脂蛋白B 生产不是由其合成速度控制，而是由其数量控制。 新合成的apoB和apoB从 降解分泌途径尚不清楚。 为了解决这些问题， 人肝脂蛋白代谢的标准体外模型HepG2 细胞系，已被研究。 脂肪酸剥夺的HepG2细胞表现出 ER相关的apoB降解（ERAD），其中 新生多肽仅部分穿过内质网，导致暴露于 apoB结构域转移到胞质溶胶中。 结果表明， 胞质结构，蛋白酶体，降解apoB在脂肪酸剥夺 HepG2细胞 此外，蛋白酶体降解还涉及另一个 胞质组分，分子伴侣Hsp70，已知其在细胞中起作用。 将细胞蛋白质靶向降解。 使用Cell的方法 和分子生物学，以及生物物理学，这些新的结果将 扩展到确定apoB易位和降解的机制 以及调节这些过程的因素。 调查人员希望， 最终开发新的策略来减少肝脏apoB的产生， 从而降低CAD的风险。