Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein

Michiari Okuda, Kui Li, Michael R. Beard, Lori A. Showalter, Frank Scholle, Stanley M. Lemon, Steven A. Weinman

Research output: Contribution to journalArticle

735 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)366-375
Number of pages10
JournalGastroenterology
Volume122
Issue number2
DOIs
StatePublished - Jan 1 2002

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Lipid Peroxidation
Reactive Oxygen Species
Oxidative Stress
Antioxidants
Gene Expression
Hepacivirus
Mitochondria
Wounds and Injuries
Proteins
Carbon Tetrachloride
Chronic Hepatitis C
Virus Diseases
Hepatitis C
Electron Transport
Cytochromes c
Transgenic Mice
Cell Line
Liver
Hepatitis C virus nucleocapsid protein
Therapeutics

All Science Journal Classification (ASJC) codes

  • Gastroenterology

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Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein. / Okuda, Michiari; Li, Kui; Beard, Michael R.; Showalter, Lori A.; Scholle, Frank; Lemon, Stanley M.; Weinman, Steven A.

In: Gastroenterology, Vol. 122, No. 2, 01.01.2002, p. 366-375.

Research output: Contribution to journalArticle

Okuda, Michiari ; Li, Kui ; Beard, Michael R. ; Showalter, Lori A. ; Scholle, Frank ; Lemon, Stanley M. ; Weinman, Steven A. / Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein. In: Gastroenterology. 2002 ; Vol. 122, No. 2. pp. 366-375.
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