Steatosis correlates with hepatic expression of death receptors and activation of nuclear factor-κB in chronic hepatitis C

Abstract

Background: Steatosis is recognized as a predictor of the severity as well as the progression of fibrosis in chronic hepatitis C. The mechanisms that cause increased hepatocellular injury associated with steatosis remain largely unknown. Methods: We studied the correlation of hepatic expression of death receptors: Fas and tumour necrosis factor-α receptor 1 (TNF-R1), and downstream caspase (caspase-3) with hepatic steatosis by immunohistochemical study in chronic hepatitis C and determined the role of nuclear factor-κB (NF-κB). Results: Ninety patients (49 males and 41 females, mean age of 50.5 ± 10.4 years, genotype 1 or 2) with chronic hepatitis C virus infection were recruited. The factors associated with steatosis grade were body mass index (P=0.004) and fibrosis stage (P=0.034). Moderate/ severe steatosis was an independent variable associated with advanced fibrosis stage by stepwise logistic regression analysis. The expression of immunoreactivity for Fas, TNF-R1 and active caspases-3 in liver tissues was significantly correlated with the steatosis grade (P <0.001, P <0.001 and P <0.001 respectively). The extent of active caspases-3 correlated significantly with the expression of Fas (r = 0.659, P <0.001) and TNF-R1 (r = 0.617, P <0.001). NF-κB p65 expression correlated significantly with the extent of Fas (r = 0.405, P < 0.001), TNF-R1 (r = 0.448, P = 0.002) and active caspase-3 (r = 0.313, P = 0.003), and correlated with steatosis grade (P<0.001) but not with inflammatory and fibrosis scores. Conclusion: Our observations suggest a mechanism whereby steatosis contributes to the progression of liver injury in chronic hepatitis C through upregulation of death receptors and activation of NF-κB. © 2008 The Authors. Journal compilation © 2008 Blackwell Munksgaard.