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。

• 批准号: 8452000
• 负责人: CHENG JI
• 金额: $ 34.39万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-20 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8452000
• 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; Endothelial Cells; Fatty Liver; Folate; Glucose Transporter; Goals; HIV; HIV Protease Inhibitors; Hepatic Stellate Cell; Hepatocyte; Hepatotoxicity; Highly Active Antiretroviral Therapy; Human; Hyperhomocysteinemia; In Vitro; Infection; 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; liver injury; multicatalytic endopeptidase complex; protective effect; public health relevance; response

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.

描述（由申请人提供）：HIV蛋白酶抑制剂（HIV PI）用于高度抗逆转录病毒疗法（HAART）。但是，艾滋病毒PI通常与肝脏损害的发展有关。 HIV蛋白酶抑制剂诱导的肝损伤的机制的定义很差。新兴的证据表明，HIV PI诱导内质网（ER）应激反应，该反应已显示在包括坏死症，肝细胞死亡和脂肪肝的肝功能障碍中起着至关重要的作用。我们先前观察到，饮酒是在易感性和进展的易感性中得到良好认可的辅助因素，诱导了肝脏中的高粒性安全性结膜血症和ER应激反应。艾滋病毒感染的患者很大一部分滥用酒精，逻辑上考虑酒精和艾滋病毒PI之间的相互作用有助于严重的肝脂肪变性和损伤。我们假设HIV PI和酒精对ER胁迫和脂质代谢产生增强的影响，这会使肝损伤恶化。我们建议探索原代小鼠和人肝细胞中HIV PI诱导的ER应激反应，并在体内研究其与酒精中酒精的致病作用相互作用。我们的具体目的是：（1）比较慢性配对和酒精喂养的小鼠体内单一或联合HIV PI治疗引起的ER应力和肝损伤，并通过检查HIV PI-PI诱导的HIV PI-PI诱导的添加性或协同作用，从而通过在主要小鼠和人肝细胞中均可在原发性小鼠和人类肝细胞中进行培养和培养培养基的培养基和人类培养基，并通过培养HEP和培养物质的培养基和培养物。 （2）确认在口口相传的小鼠中，在有或不存在模仿人类抗逆转录病毒疗法的单一或联合HIV PI的情况下，在口口相传的小鼠中； （3）研究HIV PI和酒精通过监测钙在原代小鼠和人肝细胞中释放到细胞质中的核心应力反应的协同机制，并通过检查蛋白酶体的活性以及葡萄糖转运蛋白在肝细胞中施用HIV PIS的葡萄糖转运蛋白的表达和活性； （4）隔离非核细胞（肝星细胞，库普弗细胞和内皮细胞），并在这些细胞类型中分化HIV PI-或酒精诱导的ER应激反应； （5）在体外和体内确定保护性分子伴侣（例如4-苯基丁酸）在HIV诱导的ER应激和肝损伤中的有效性。该项目将更好地了解HIV蛋白酶抑制剂的肝毒性，并更好地改善感染HIV感染患者的护理的策略。

项目成果

Differences in betaine-homocysteine methyltransferase expression, endoplasmic reticulum stress response, and liver injury between alcohol-fed mice and rats.

• DOI: 10.1002/hep.23391
• 发表时间: 2010-03
• 期刊: HEPATOLOGY
• 影响因子: 13.5
• 作者: Shinohara, Masao;Ji, Cheng;Kaplowitz, Neil
• 通讯作者: Kaplowitz, Neil

Human immunodeficiency virus protease inhibitors modulate Ca2+ homeostasis and potentiate alcoholic stress and injury in mice and primary mouse and human hepatocytes.

• DOI: 10.1002/hep.25702
• 发表时间: 2012-08
• 期刊: HEPATOLOGY
• 影响因子: 13.5
• 作者: Kao, Eddy;Shinohara, Masao;Feng, Min;Lau, Mo Yin;Ji, Cheng
• 通讯作者: Ji, Cheng

Expression of the 78 kD glucose-regulated protein is induced by endoplasmic reticulum stress in the development of hepatopulmonary syndrome.

• DOI: 10.1016/j.gene.2013.11.065
• 发表时间: 2014-03-01
• 期刊: Gene
• 影响因子: 3.5
• 作者: Zhang H;Lv M;Jia J;Zhao Z;Zhang L;Lai L;Wu Y;Li B;Li C;Ji J;Tian X;Liu Y;Li X;Pang H;Guo J;Wang L;Fan Y;Zhang C;Han D;Ji C
• 通讯作者: Ji C