Endoplasmic reticulum stress induced by hepatitis B virus X protein enhances cyclo-oxygenase 2 expression via activating transcription factor 4

Chronic hepatitis B is a disease of the liver that can progress to cirrhosis and liver cancer. The HBx (hepatitis B virus X) protein of hepatitis B virus is a multifunctional regulator that induces ER (endoplasmic reticulum) stress by previously unknown mechanisms. ER stress plays a critical role in inflammatory induction and COX2 (cyclo-oxygenase 2) is an important mediator of this inflammation. In the present study, we demonstrate the molecular mechanisms of HBx on induction of ER stress and COX2 expression. In addition, HBx reduced expression of enzymes which are involved in mitochondrial beta-oxidation of fatty acids and the mitochondrial inner membrane potential. The reduction in intracellular ATP levels by HBx induced the unfolded protein response and COX2 expression through the eIF2 alpha (eukaryotic initiation factor 2 alpha)/ATF4 (activating transcription factor 4) pathway. We confirmed that ATF4 binding to the COX2 promoter plays a critical role in HBx-mediated COX2 induction. The results of the present study suggest that HBV infection contributes to induction of hepatic inflammation through dysfunction of cellular organelles including the ER and mitochondria.