HIV Protease Inhibitors and Hepatic Lipid Dysregulation

HIV 蛋白酶抑制剂和肝脂质失调

• 批准号: 6861103
• 负责人: PHILLIP B HYLEMON
• 金额: $ 33.23万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6861103
• 关键词: DNA binding protein; amprenavir; antiAIDS agent; cholanate compound; cholesterol; drug adverse effect; indinavir; intracellular transport; laboratory mouse; laboratory rat; lipid metabolism; liver metabolism; male; nelfinavir; protease inhibitor; protein metabolism; ritonavir

DESCRIPTION (provided by applicant): Human immunodeficiency virus (HIV) infection is a growing epidemic within today's world population. Highly active antiretroviral therapies (HAART) are becoming increasingly effective at decreasing or even eliminating the serum viral load of HIV positive individuals, resulting in increased life spans. Unfortunately, long-term harmful side effects (hyperlipidemias, lipodystrophy and insulin resistance) of HAART therapeutics are becoming evident. The mechanism(s) by which HIV protease inhibitors (PI) therapy leads to dysregulation of sterol and lipid metabolism is unclear. The liver is the major organ responsible for maintaining lipid homeostasis in the body. The proposed experiments in this new application will explore the mechanism(s) by which different HIV PIs alter hepatic cholesterol, bile acid and fatty acid metabolism. The specific aims of this application are: 1) Determine the effects of the most commonly used HIV PI (ritonavir, indinavir, nelfinavir, Iopinavir, atazanavir) on cholesterol, bile acids and fatty acid metabolism using primary adult rat hepatocytes as a model system; 2) Determine the effects of HIV PI on hepatic cholesterol, fatty acid, and bile acid metabolism and lipoprotein profiles in a mouse in vivo model 3) Elucidate the mechanism(s) where by indinavir (and other HIV PIs) alters hepatic cholesterol and bile acid metabolism in primary rat hepatocytes. Test the hypothesis that HIV PIs alters the intracellular movement of cholesterol and/or protein turnover rates of sterol responsive element binding proteins (SREBPs). Knowledge of how HIV PI alter lipid metabolism may allow for more effective, long term approaches for treating HIV infected individuals.

描述（由申请人提供）：人类免疫缺陷病毒（HIV）感染是当今世界人口中日益增长的流行病。高度活跃的抗逆转录病毒疗法（HAART）在减少甚至消除HIV阳性个体的血清病毒载量方面变得越来越有效，从而导致寿命增加。不幸的是，HAART治疗剂的长期有害副作用（高脂症，脂肪营养不良和胰岛素抵抗）变得明显。 HIV蛋白酶抑制剂（PI）疗法导致固醇和脂质代谢失调的机制尚不清楚。肝脏是负责维持体内脂质稳态的主要器官。该新应用中提出的实验将探讨不同的HIV PIS改变肝胆固醇，胆汁酸和脂肪酸代谢的机制。该应用的具体目的是：1）确定最常用的HIV PI（Ritonavir，Indinavir，Nelfinavir，Iopinavir，Atazanavir）对胆固醇，胆汁酸和脂肪酸代谢使用原代成年大鼠肝细胞作为模型系统的影响； 2）确定HIV PI对肝胆固醇，脂肪酸和胆汁酸代谢和脂蛋白谱的影响在体内模型3）中阐明了该机制，其中indinavir（and其他HIV PIS）在原代含量中通过乙醇（和其他HIV PIS）改变了肝胆固醇和胆汁酸性代谢。测试HIV PI会改变固醇反应元件结合蛋白（SREBPS）的胆固醇和/或蛋白质更新速率的细胞内运动的假设。了解HIV PI如何改变脂质代谢可能会允许更有效，长期治疗艾滋病毒感染的个体。