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

描述(由申请人提供)： 作为高效抗逆转录病毒治疗(HAART)的核心成分，HIV蛋白酶抑制物(PI)的肝脏脂毒性已成为临床上的主要关注问题，尤其是在饮酒患者中。酒精滥用本身也会产生肝脏毒性，在目前的治疗下，它是艾滋病毒患者肝脏损伤的最重要的共病风险因素之一。尽管这一问题的普遍存在及其对HIV患者的生活质量和持续治疗的严重影响，但酒精加剧HIV PI诱导的肝脏脂肪毒性的机制尚未确定。这项建议的目的是研究酒精使用/滥用对HIV PI诱导的肝脏脂肪毒性的潜在影响，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通过激活内质网应激，从而破坏脂质平衡，诱导肝细胞凋亡，从而相加地诱导肝脏脂肪毒性。在本研究中，我们将(1)确定酒精对HIV PI诱导的内质网应激激活的影响，(2)确定ER应激在酒精和HIV PI诱导的肝脏脂毒性中的作用，(3)确定酒精促进HIV PI诱导的ER应激和肝脏脂毒性的机制。本研究的长期目标是了解酒精和HAART引起肝脏脂肪毒性的分子/细胞机制。随着感染艾滋病毒的患者数量继续增加，艾滋病毒患者的肝脏损伤负担预计将增加。了解酒精和HIVPI引起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诱导的肝脏脂肪毒性的新的细胞机制，从而增强我们对HAART相关肝病机制的理解，并为未来新的预防和治疗策略的开发提供新的信息。

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.