HIV Protease Inhibitors and Hepatic Lipid Dysregulation

描述(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严重的流行病。高效抗逆转录病毒疗法(HAART)在减少甚至消除艾滋病毒阳性患者的血清病毒载量方面正变得越来越有效，从而延长了寿命。不幸的是，HAART疗法的长期有害副作用(高脂血症、脂肪营养不良和胰岛素抵抗)正在变得明显。艾滋病毒蛋白水解酶抑制剂(PI)治疗导致类固醇和脂类代谢失调的机制(S)尚不清楚。肝脏是维持体内脂质平衡的主要器官。在这一新应用中拟议的实验将探索不同艾滋病毒PI改变肝脏胆固醇、胆汁酸和脂肪酸代谢的机制(S)。本应用的具体目的是：1)以原代成年大鼠肝细胞为模型系统，测定最常用的艾滋病毒PI(利托那韦、英地那韦、奈非那韦、爱彼那韦、阿扎那韦)对胆固醇、胆汁酸和脂肪酸代谢的影响；2)测定HIV PI对小鼠肝脏胆固醇、脂肪酸和胆汁酸代谢的影响及脂蛋白谱；3)阐明Indinavir(和其他HIV PI)改变大鼠肝细胞胆固醇和胆汁酸代谢的机制(S)。测试HIV PI改变细胞内胆固醇的移动和/或固醇反应元件结合蛋白(SREBPs)的蛋白质周转率的假设。了解HIV PI如何改变脂代谢可能会为治疗HIV感染者提供更有效、更长期的方法。

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.