Alcohol Potentiates HIV Protease Inhibitor‐induced ER Stress and Hepatic Lipotoxicity (1001.3)

Alcohol consumption, which is highly prevalent in HIV‐infected individuals, has been associated with the amplification of liver toxicities induced by HIV protease inhibitors (PIs). We have demonstrated that HIV PI‐induced endoplasmic reticulum (ER) stress is linked to the dysregulation of hepatic lipid metabolism. However, little is known about the mechanistic pathways by which alcohol promotes HIV PI‐induced hepatic lipotoxicity. The aim of this study was to examine the cellular mechanisms by which alcohol promotes HIV PI‐induced hepatic lipotoxicity. Methods: Primary hepatocytes isolated from rat, wild type mouse or CHOP‐/‐ mouse were treated with individual HIV PIs with or without alcohol. Activation of the ER stress was determined by real time RT‐PCR and Western Blot. Apoptosis was detected by Annexin V‐FITC/propidium iodide staining. Intracellular lipid accumulation was determined by nile red staining. Results: Alcohol and HIV PIs synergistically induced ER stress, lipid accumulation and apoptosis in primary hepatocytes. Both alcohol and HIV PI‐induced lipid accumulation and apoptosis were significantly reduced in CHOP‐/‐ hepatocytes. Conclusions: Activation of the ER stress response is a key cellular mechanism underlying alcohol and HIV PI‐induced hepatotoxicity. Inhibition of ER stress activation may represent a new strategy to prevent alcohol and HIV PI‐associated hepatic lipotoxicity.Grant Funding Source: VA Merit Award