HIV Protease Inhibitors and Hepatic Lipid Dysregulation

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严重的流行病。高效抗逆转录病毒疗法（HAART）在降低甚至消除HIV阳性个体的血清病毒载量方面变得越来越有效，从而延长寿命。不幸的是，HAART疗法的长期有害副作用（高血压、脂肪代谢障碍和胰岛素抵抗）变得越来越明显。HIV蛋白酶抑制剂（PI）治疗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。这项新应用中的拟议实验将探索不同HIV PI改变肝脏胆固醇、胆汁酸和脂肪酸代谢的机制。本申请的具体目的是：1）确定最常用的HIV PI的效果（利托那韦、茚地那韦、奈非那韦、碘匹那韦、阿扎那韦）对胆固醇、胆汁酸和脂肪酸代谢的影响，使用原代成年大鼠肝细胞作为模型系统; 2）测定HIV PI对肝脏胆固醇、脂肪酸、和胆汁酸代谢和脂蛋白谱3）阐明茚地那韦（和其他HIV PI）改变原代大鼠肝细胞中肝胆固醇和胆汁酸代谢的机制。检验HIV PI改变胆固醇的细胞内运动和/或固醇反应元件结合蛋白（SREBP）的蛋白质周转率的假设。HIV PI如何改变脂质代谢的知识可以允许更有效的，长期的方法来治疗HIV感染者。

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.