Impact of Alcohol on HIV Protease Inhibitor-induced ER Stress and Lipotoxicity

描述（由申请人提供）： HIV蛋白酶抑制剂（PI）是高效抗逆转录病毒治疗（HAART）的核心成分，与PI相关的肝脏脂毒性已成为临床上的主要关注点，尤其是在饮酒患者中。酒精滥用也会产生肝毒性，是目前治疗下HIV患者肝损伤的最重要的共病危险因素之一。尽管这一问题的普遍性及其对HIV患者生活质量和持续治疗的严重影响，但酒精加剧HIV PI诱导的肝脂毒性的机制尚未确定。本提案的目的是研究酒精使用/滥用对HIV PI诱导的肝脏脂毒性的潜在影响，并进一步阐明潜在的细胞/分子机制。本研究的中心假设是酒精和HIV PI通过激活ER应激，随后破坏脂质稳态并诱导肝细胞凋亡，从而叠加诱导肝脂毒性。在这项研究中，我们将（1）确定酒精对HIV PI诱导的ER应激激活的影响，（2）确定ER应激在酒精和HIV PI诱导的肝脂毒性中的作用，（3）确定酒精促进HIV PI诱导的ER应激和肝脂毒性的机制。本研究的长期目标是了解酒精和HAART诱导肝脂毒性的分子/细胞机制。随着艾滋病毒感染者人数的持续增加，预计艾滋病毒感染者的肝损伤负担将增加。了解酒精和HIV PI诱导肝毒性的机制具有重要的临床意义。这些目标的完成将有助于确定酒精和HIV PI诱导的肝脏脂毒性的新细胞机制，从而提高我们对HAART相关肝病机制的理解，并为未来开发新的预防和治疗策略提供新的信息。

DESCRIPTION (provided by applicant): The hepatic lipotoxicity specifically associated with HIV protease inhibitors (PIs), the core component of highly active anti-retroviral therapy (HAART), has become a major concern in the clinic, especially in patients who consume alcohol. Alcohol abuse, which alone also produces liver toxicity, is one of the most important co-morbid risk factors for liver injury in HIV patient under current therapy. Despite the prevalence of this problem and its serious impact on the quality of life and continued therapy in HIV patients, the mechanism by which alcohol exacerbates HIV PI-induced hepatic lipotoxicity has not been identified. The goal of this proposal is to examine the potential impact of alcohol use/abuse on HIV PI- induced hepatic lipotoxicity and further elucidate the underlying cellular/molecular mechanisms. The central hypothesis of this study is that alcohol and HIV PIs additively induce hepatic lipotoxicity by activating the ER stress, subsequently disrupting lipid homeostasis and inducing apoptosis in hepatocytes. In this study, we will (1) determine the impact of alcohol on HIV PI-induced activation of ER stress, (2) determine the role of ER stress in alcohol and HIV PI-induced hepatic lipotoxicity and (3) identify the mechanism by which alcohol promotes HIV PI-induced ER stress and hepatic lipotoxicity. The long-term goal of this research is to understand the molecular/cellular mechanisms by which alcohol and HAART induce hepatic lipotoxicity. The burden of liver injury in HIV patients is expected to increase as the number of patients living wit HIV continues to rise. Understanding the mechanism by which alcohol and HIV PIs induce hepatotoxicity is of great clinical importance. Completion of these objectives will help identify new cellular mechanisms of alcohol and HIV PI-induced hepatic lipotoxicity, thereby enhancing our understanding of the mechanisms of HAART-associated liver diseases and providing novel information for the future development of new preventative and therapeutic strategies.