Hepatitis C virus‐core and non structural proteins lead to different effects on cellular antioxidant defenses

Abstract

Chronic hepatitis C virus (HCV) infection leads to increased oxidative stress in the liver. Hepatic antioxidant enzymes provide an important line of defense against oxidative injury. To understand the antioxidant responses of hepatocytes to different HCV proteins, we compared changes in antioxidative enzymes in HCV-core and HCV-nonstructural protein expressing hepatocyte cell lines. We found that expression of HCV-core protein in hepatocyte cell lines leads to increased oxidative stress as determined by increased in the oxidant-sensitive probe 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate (CM-DCFH(2)) fluorescence, decreased reduced glutathione (GSH), and increased oxidation of thioredoxin (Trx). Although the expression of HCV-nonstructural (HCV-NS) proteins led to increased oxidative stress as well, the antioxidant enzymatic responses were different. Over-expression of HCV-NS proteins increased antioxidant enzymes (MnSOD and catalase), heme oxygenase-1 (HO-1), and GSH, indicating different mechanism(s) of prooxidative activity than HCV-core protein. Our findings show that different HCV proteins induce different antioxidant defense responses in hepatocytes. These findings may facilitate understanding the interaction of different HCV proteins with infected liver cells and help identify possible factors contributing to hepatocyte damage during HCV infection.

Role of free radicals in liver diseases

“…In addition, proteins of HCV can increase ROS and RNS in the infected cells; proteins of the HCV core have been shown to augment the oxidative and nitrosative stress, lipid peroxidation, oxidized thioredoxin, and antioxidant gene expression such as that of metallothionein family proteins and manganese superoxide dismutase (MnSOD) as well as to enhance sensitivity to toxins such as ethanol and CCl 4 [81,[91][92][93][94][95]. HCV core gene expression diminishes the intracellular GSH levels and the mitochondrial NADPH content that are associated with increased uptake of calcium and oxidative stress generation at complex I in mitochondria, providing an action mechanism for HCVinduced ROS production [42,91,92,96].…”

“…HCV core gene expression diminishes the intracellular GSH levels and the mitochondrial NADPH content that are associated with increased uptake of calcium and oxidative stress generation at complex I in mitochondria, providing an action mechanism for HCVinduced ROS production [42,91,92,96]. On the contrary, core protein modulates the production of cytokines and host enzymes, such as cyclooxygenase-2 and inducible nitric oxide synthase (iNOS), which can increase ROS and RNS [97][98][99][100][101][102][103].…”

“…Host antioxidant defenses, such as GSH, catalase, MnSOD, and heme oxygenase-1, are augmented, suggesting adaptation to ROS/RNS stress [92,104,105].…”

Reciprocal Effects of Micro-RNA-122 on Expression of Heme Oxygenase-1 and Hepatitis C Virus Genes in Human Hepatocytes

“…The mechanisms underlying HCV-associated liver injury are imperfectly understood. Several lines of evidence indicate that increased oxidative stress is an important pathogenetic mechanism in CHC (3)(4)(5)(6)(7)(8)(9). HCV core and nonstructural proteins have been shown to cause transcriptional modulation as either trans-activators or trans-suppressors of cellular signaling pathways through interference with intracellular oxidation/reduction reactions (10)(11)(12).…”

Redox regulation of hepatitis C in nonalcoholic and alcoholic liver

“…For example, HCV core protein has been shown to increase the levels of ROS/RNS, oxidized thioredoxin, lipid peroxidation products, and antioxidant gene expression, such as that of manganese superoxide dismutase (MnSOD) and metallothioneine family proteins, and to enhance the sensitivity to toxins such as ethanol and CCl 4 [38, [60][61][62][63][64][65]. In terms of a mechanism, HCV core gene expression decreases the intracellular/mitochondrial GSH levels and the mitochondrial NADPH levels, which are accompanied by increased Ca 2+ uptake as well as ROS generation at Complex I in mitochondria [60][61][62]66]. Although whether the mitochondrial, cytosolic, and/or total intracellular GSH are decreased in a consistent and predictable manner is still unclear, only the mitochondrial, and not the total liver GSH, was altered with the HCV core protein in a recent study [60].…”