Acrolein Exacerbates HAART–Induced Apoptotic Death in Hepatocytes by Enhancing Transcriptionally Permissive Epigenetic Modifications at FasL Promoter

Abstract

Highly active antiretroviral therapy (HAART) ‐ associated hepatotoxicity is becoming a major clinical problem leading to morbidity, mortality and treatment discontinuation in HIV patient. Environmental/dietary factors are known to significantly impact general health as well as therapeutic outcomes. Acrolein is one such common dietary and environmental pollutant and is also generated endogenously by cellular metabolism. The present study examines the hepatotoxic interactions of acrolein with HAART drug, azidothymidine (AZT).Human hepatoma cells (HepG2) as well as rat primary hepatocytes were used to examine the cytotoxic effects of acrolein (ACR) and AZT treatment either individually or in combination (AZT+ACR). Data showed that acrolein enhances expression of FasL gene, leading to increased apoptosis in AZT treated cells. Chromatin immunoprecipitation (ChIP) analysis revealed that ACR+AZT induced enhanced FasL transcription was mediated by increased in promoter histone H3K9 acetylation allowing recruitment of NFkB and RNA Polymerase II at the FasL promoter. Notably, acrolein scavenger, hydralazine significantly attenuated acrolein induced transcriptionally permissive modifications at the FasL promoter preventing FasL expression and hepatocyte cell death. Overall, the data suggest that environmental and/or dietary exposure to acrolein can induce chromatin modifications and further exacerbate the hepatotoxic effects of HAART medication affecting treatment options for HIV patients. This work was supported by NIH grants.