BACKGROUND & AIMS: The mechanisms of liver injury in chronic hepatitis C virus (HCV) infection are poorly understood. Indirect evidence suggests that oxidative stress and mitochondrial injury play a role. The aim of this study was to determine if the HCV core protein itself alters mitochondrial function and contributes to oxidative stress. METHODS: HCV core protein was expressed in 3 different cell lines, and reactive oxygen species (ROS) and lipid peroxidation products were measured. RESULTS: Core expression uniformly increased ROS. In 2 inducible expression systems, core protein also increased lipid peroxidation products and induced antioxidant gene expression as well. A mitochondrial electron transport inhibitor prevented the core-induced increase in ROS. A fraction of the expressed core protein localized to the mitochondria and was associated with redistribution of cytochrome c from mitochondrial to cytosolic fractions. Sensitivity to oxidative stress was also seen in HCV transgenic mice in which increased intrahepatic lipid peroxidation products occurred in response to carbon tetrachloride. CONCLUSIONS: Oxidative injury occurs as a direct result of HCV core protein expression both in vitro and in vivo and may involve a direct effect of core protein on mitochondria. These results provide new insight into the pathogenesis of hepatitis C and provide an experimental rationale for investigation of antioxidant therapy.
BACKGROUND & AIMS: The mechanisms of liver injury in chronic hepatitis C virus (HCV) infection are poorly understood. Indirect evidence suggests that oxidative stress and mitochondrial injury play a role. The aim of this study was to determine if the HCV core protein itself alters mitochondrial function and contributes to oxidative stress. METHODS:HCV core protein was expressed in 3 different cell lines, and reactive oxygen species (ROS) and lipid peroxidation products were measured. RESULTS: Core expression uniformly increased ROS. In 2 inducible expression systems, core protein also increased lipid peroxidation products and induced antioxidant gene expression as well. A mitochondrial electron transport inhibitor prevented the core-induced increase in ROS. A fraction of the expressed core protein localized to the mitochondria and was associated with redistribution of cytochrome c from mitochondrial to cytosolic fractions. Sensitivity to oxidative stress was also seen in HCVtransgenic mice in which increased intrahepatic lipid peroxidation products occurred in response to carbon tetrachloride. CONCLUSIONS:Oxidative injury occurs as a direct result of HCV core protein expression both in vitro and in vivo and may involve a direct effect of core protein on mitochondria. These results provide new insight into the pathogenesis of hepatitis C and provide an experimental rationale for investigation of antioxidant therapy.
Authors: Wenyu Lin; Wei-Lun Tsai; Run-Xuan Shao; Guoyang Wu; Lee F Peng; Lydia L Barlow; Woo Jin Chung; Leiliang Zhang; Hong Zhao; Jae-Young Jang; Raymond T Chung Journal: Gastroenterology Date: 2010-03-12 Impact factor: 22.682
Authors: Yong-Han Paik; Jonghwa Kim; Tomonori Aoyama; Samuele De Minicis; Ramon Bataller; David A Brenner Journal: Antioxid Redox Signal Date: 2014-01-24 Impact factor: 8.401
Authors: Ezra Gabbay; Ehud Zigmond; Orit Pappo; Nila Hemed; Mina Rowe; George Zabrecky; Robert Cohen; Yaron Ilan Journal: World J Gastroenterol Date: 2007-10-28 Impact factor: 5.742