HIV protease inhibitors (PIs) are the core components of the highly active anti-retroviral therapy (HAART), which has changed HIV infection from an invariably lethal to a manageable chronic condition. However, hepatic lipotoxicity, a process of hepatocellular dysfunction and injury induced by excess lipid accumulation, specifically associated with HIV PIs has become a major concern in the clinic, especially in patients who consume alcohol. Alcohol abuse, which is very common in HIV-1 infected patients, is one of the most important co-morbid risk factors for liver injury and has been associated with the occurrence of serious metabolic syndrome and subsequent discontinuation of HAART in HIV patients. Despite the prevalence of this problem, the cellular mechanisms by which alcohol exacerbates HAART- induced hepatic lipotoxicity remain to be identified. Previous studies have identified that activation of endoplasmic reticulum (ER) stress represents an important mechanism underlying HIV PI-induced inflammation and hepatic lipotoxicity. It also has been reported that ER stress is a critical contributor to alcohol-induced liver injury. Recent studies further indicate that activation of Kupffer cells (KCs), the resident liver macrophages, has a pivotal role in the pathogenesis of alcohol-induced inflammation and hepatic lipotoxicity. Alcohol-induced activation of the inflammasome in KCs is involved in hepatic inflammation, steatosis and injury. The inflammasome activates caspase-1, which cleaves pro-IL-1? into the bioactive IL-1?. IL-1? acts in an autocrine/paracrine manner through type I IL-1 receptor to activate inflammatory response. Reports show that the levels of proinflammatory cytokine, IL-1?, in patients with alcoholic liver disease (ALD) are increased. We hypothesize that alcohol promotes HIV PI-induced hepatic lipotoxicity by activating ER stress in hepatocytes and inflammasome in KCs, subsequently disrupting lipid homeostasis and inducing apoptosis in hepatocytes. We wish to define the role of ER stress in alcohol and HIV PI-induced hepatic lipotoxicity. Also, we will study the effect of alcohol and HIV PI on inflammasome activation in KCs. Finally, we intend to detail the impact of inflammasome activation in KCs on alcohol and HIV PI-induced hepatic lipotoxicity. We will approach our study with the following research aims:
Specific Aim 1 - To define the role of ER stress in alcohol- and HIV PI-induced hepatic lipotoxicity.
Specific Aim 2 - To examine the effect of alcohol and HIV PI on inflammasome activation in KCs.
Specific Aim 3 - To characterize the impact of inflammasome activation in KCs on alcohol and HIV PI-induced hepatic lipotoxicity.
The burden of liver injury in HIV patients is expected to increase as the number of patients living with HIV continues to rise. Understanding the mechanism by which alcohol and HIV PIs promote hepatotoxicity is of great clinical importance. Completion of this proposed study will help identify the 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.
