Effect of HIV protease inhibitor on alcohol induced ER stress and liver injury.

HIV 蛋白酶抑制剂对酒精诱导的 ER 应激和肝损伤的影响。

基本信息

批准号：
7840594
负责人：
CHENG JI
金额：
$ 37.15万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-20 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7840594
关键词：
AIDS/HIV problem Acute Aftercare Alcohol abuse Alcohol consumption Alcohols Animal Feed Biological Availability Calcium Caring Cell Death Cells Chronic Culture Media Cytosol Development Diet Disease Effectiveness Endoplasmic Reticulum Endothelial Cells Fatty Liver Folate Glucose Transporter Goals HIV HIV Protease Inhibitors Hepatic Hepatic Stellate Cell Hepatocyte Hepatotoxicity Highly Active Antiretroviral Therapy Human Hyperhomocysteinemia In Vitro Infection Injury Insulin Resistance Kupffer Cells Laboratories Liver Liver Dysfunction Liver diseases Methionine Molecular Chaperones Monitor Mus Obesity Pathogenesis Patients Phenylbutyrates Plasma Play Predisposition Reporting Role alcohol effect antiretroviral therapy biological adaptation to stress cell injury cell type endoplasmic reticulum stress feeding improved in vivo lipid metabolism multicatalytic endopeptidase complex protective effect public health relevance response

项目摘要

DESCRIPTION (provided by applicant): HIV protease inhibitors (HIV PIs) are used in the highly ctive antiretroviral therapy (HAART). However, HIV PIs are often associated with development of liver damages. The mechanisms of the HIV protease inhibitor- induced liver injury are poorly defined. Emerging evidence indicates that the HIV PIs induce endoplasmic reticulum (ER) stress response which has been shown to play an essential role in liver dysfunction including necroinflammation, hepatic cell death and fatty liver. We previously observed that alcohol consumption, which is a well-recognized co-factor in susceptibility to the infection and progression of HIV, induced hyperhomocysteinemia and ER stress response in the liver. A significant proportion of HIV infected patients abuse alcohol and it is logical to consider that an interplay between the effects of alcohol and HIV PIs contributes to severe hepatic steatosis and injury. We hypothesize that HIV PI and alcohol exert a potentiated effect on ER stress and lipid metabolism which worsens liver injury. We propose to explore the HIV PI-induced ER stress response in both primary mouse and human hepatocytes and to investigate in vivo its interactions with pathogenic effects of alcohol in animals fed alcohol. Our specific aims are: (1) to compare ER stress and hepatic injury induced by single or combined HIV PI treatments in vivo in chronic pair- and alcohol-fed mice, and to assess additive or synergistic effects by examining HIV PI-induced ER stress response in vitro in both primary mouse and human hepatocytes and by monitoring bioavailability of HIV PIs in plasma and culture medium of hepatocytes; (2) to confirm ER stress response in mice fed orally a high methionine low folate diet in the presence or absence of single or combined HIV PIs that mimic the antiretroviral therapy in human; (3) to study synergistic mechanisms of ER stress response by HIV PIs and by alcohol through monitoring calcium releasing into the cytosol in primary mouse and human hepatocytes and through examining proteasome activities and expression and activities of glucose transporters in hepatocytes administered HIV PIs; (4) to isolate non-parenchymal cells (hepatic stellate cells, Kupffer cells, and endothelial cells) and differentiate HIV PI- or alcohol-induced ER stress response in these cell types; (5) to determine in vitro and in vivo the effectiveness of protective molecular chaperones (e.g. 4-phenylbutyrate ) in HIV PI- induced ER stress and liver injury. This project will provide a better understanding of the hepatotoxicity of HIV protease inhibitors and better strategies to improve care for HIV-infected patients. PUBLIC HEALTH RELEVANCE: HIV protease inhibitors (HIV PIs) used in highly active effective ntiretroviral therapies (HAART) induce liver damages in patients with HIV/AIDS, especially in the patients who consume alcohol. We have identified that either alcohol or HIV PIs induce endoplasmic reticulum (ER) stress that plays an important role in a variety of disorders including insulin resistance, obesity, and liver disease. Understanding of additive/synergistic effects of HIV PIs and alcohol on the ER stress that worsens liver injury will provide better strategies to improve care for HIV-infected patients.

描述（由申请人提供）：HIV蛋白酶抑制剂（HIV PI）用于高活性抗逆转录病毒疗法（HAART）。然而，HIV PI 通常与肝损伤的发生有关。 HIV蛋白酶抑制剂引起的肝损伤的机制尚不清楚。新的证据表明，HIV PI 会诱导内质网 (ER) 应激反应，这已被证明在肝功能障碍（包括坏死性炎症、肝细胞死亡和脂肪肝）中发挥重要作用。我们之前观察到，饮酒是艾滋病毒感染和进展易感性的一个公认的辅助因素，它会诱发肝脏高同型半胱氨酸血症和内质网应激反应。很大一部分 HIV 感染患者滥用酒精，因此可以合理地认为，酒精和 HIV PI 之间的相互作用会导致严重的肝脏脂肪变性和损伤。我们假设 HIV PI 和酒精对 ER 应激和脂质代谢产生增强作用，从而加重肝损伤。我们建议在原代小鼠和人类肝细胞中探索 HIV PI 诱导的 ER 应激反应，并在喂食酒精的动物体内研究其与酒精致病作用的相互作用。我们的具体目标是：(1) 在长期配对和酒精喂养的小鼠体内比较单一或联合 HIV PI 治疗引起的 ER 应激和肝损伤，并通过检查 HIV PI 诱导的 ER 应激来评估相加或协同效应在原代小鼠和人类肝细胞中进行体外反应，并通过监测肝细胞血浆和培养基中 HIV PI 的生物利用度； (2) 在存在或不存在模拟人类抗逆转录病毒治疗的单一或组合 HIV PI 的情况下，确认口服高蛋氨酸低叶酸饮食的小鼠的 ER 应激反应； (3) 通过监测原代小鼠和人肝细胞中钙释放到细胞质中，并通过检查施用 HIV PI 的肝细胞中的蛋白酶体活性以及葡萄糖转运蛋白的表达和活性，研究 HIV PI 和酒精对 ER 应激反应的协同机制； (4) 分离非实质细胞（肝星状细胞、库普弗细胞和内皮细胞）并区分这些细胞类型中 HIV PI 或酒精诱导的 ER 应激反应； (5) 确定体外和体内保护性分子伴侣（例如 4-苯基丁酸酯）在 HIV PI 诱导的 ER 应激和肝损伤中的有效性。该项目将更好地了解艾滋病毒蛋白酶抑制剂的肝毒性，并提供更好的策略来改善艾滋病毒感染患者的护理。公共健康相关性：高效抗逆转录病毒疗法 (HAART) 中使用的 HIV 蛋白酶抑制剂 (HIV PI) 会导致 HIV/AIDS 患者的肝损伤，尤其是饮酒的患者。我们已经发现，酒精或 HIV PI 会诱导内质网 (ER) 应激，这种应激在胰岛素抵抗、肥胖和肝病等多种疾病中发挥着重要作用。了解 HIV PI 和酒精对导致肝损伤恶化的 ER 应激的相加/协同作用，将为改善 HIV 感染患者的护理提供更好的策略。