Hepatitis C virus core protein inhibits deoxycholic acid-mediated apoptosis despite generating mitochondrial reactive oxygen species

Yuichi Hara, Keisuke Hino, Michiari Okuda, Takakazu Furutani, Isao Hidaka, Yuhki Yamaguchi, Masaaki Korenaga, Kui Li, Steven A. Weinman, Stanley M. Lemon, Kiwamu Okita

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Background. Hepatitis C virus (HCV) core protein is known to cause oxidative stress and alter apoptosis pathways. However, the apoptosis results are inconsistent, and the real significance of oxidative stress is not well known. The aim of this study was twofold. First, we wanted to confirm whether core-induced oxidative stress was really significant enough to cause DNA damage, and whether it induced cellular antioxidant responses. Second, we wanted to evaluate whether this core-induced oxidative stress and the antioxidant response to it was responsible for apoptosis changes. Methods. HCV core protein was expressed under control of the Tet-Off promoter in Huh-7 cells and HeLa cells. We chose to use deoxycholic acid (DCA) as a model because it is known to produce both reactive oxygen species (ROS) and apoptosis. Results. Core expression uniformly increased ROS and 8-hydroxy- 2′-deoxyguanosine (8-OHdG) under basal and DCAstimulated conditions. Core protein expression also increased manganese superoxide dismutase levels. Core protein inhibited DCA-mediated mitochondrial membrane depolarization and DCA-mediated activation of caspase-9 and caspase-3, despite the increase in ROS by DCA. Core protein inhibited DCA-mediated apoptosis by increasing Bcl-xL protein and decreasing Bax protein, without affecting the proportion of Bax between mitochondria and cytosol, resulting in suppression of cytochrome c release from mitochondria into cytoplasm. Conclusions. HCV core protein induces oxidative DNA damage, whereas it inhibits apoptosis that is accompanied by enhancement of ROS production. Thus, oxidative stress and apoptosis modulation by core protein are independent of each other.

Original languageEnglish (US)
Pages (from-to)257-268
Number of pages12
JournalJournal of Gastroenterology
Volume41
Issue number3
DOIs
StatePublished - Mar 1 2006
Externally publishedYes

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Deoxycholic Acid
Reactive Oxygen Species
Apoptosis
Oxidative Stress
Proteins
DNA Damage
Mitochondria
Antioxidants
bcl-2-Associated X Protein
Caspase 9
Mitochondrial Membranes
Cytochromes c
Hepatitis C virus nucleocapsid protein
HeLa Cells
Caspase 3
Cytosol
Superoxide Dismutase
Cytoplasm

All Science Journal Classification (ASJC) codes

  • Gastroenterology

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Hepatitis C virus core protein inhibits deoxycholic acid-mediated apoptosis despite generating mitochondrial reactive oxygen species. / Hara, Yuichi; Hino, Keisuke; Okuda, Michiari; Furutani, Takakazu; Hidaka, Isao; Yamaguchi, Yuhki; Korenaga, Masaaki; Li, Kui; Weinman, Steven A.; Lemon, Stanley M.; Okita, Kiwamu.

In: Journal of Gastroenterology, Vol. 41, No. 3, 01.03.2006, p. 257-268.

Research output: Contribution to journalArticle

Hara, Y, Hino, K, Okuda, M, Furutani, T, Hidaka, I, Yamaguchi, Y, Korenaga, M, Li, K, Weinman, SA, Lemon, SM & Okita, K 2006, 'Hepatitis C virus core protein inhibits deoxycholic acid-mediated apoptosis despite generating mitochondrial reactive oxygen species', Journal of Gastroenterology, vol. 41, no. 3, pp. 257-268. https://doi.org/10.1007/s00535-005-1738-1
Hara, Yuichi ; Hino, Keisuke ; Okuda, Michiari ; Furutani, Takakazu ; Hidaka, Isao ; Yamaguchi, Yuhki ; Korenaga, Masaaki ; Li, Kui ; Weinman, Steven A. ; Lemon, Stanley M. ; Okita, Kiwamu. / Hepatitis C virus core protein inhibits deoxycholic acid-mediated apoptosis despite generating mitochondrial reactive oxygen species. In: Journal of Gastroenterology. 2006 ; Vol. 41, No. 3. pp. 257-268.
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abstract = "Background. Hepatitis C virus (HCV) core protein is known to cause oxidative stress and alter apoptosis pathways. However, the apoptosis results are inconsistent, and the real significance of oxidative stress is not well known. The aim of this study was twofold. First, we wanted to confirm whether core-induced oxidative stress was really significant enough to cause DNA damage, and whether it induced cellular antioxidant responses. Second, we wanted to evaluate whether this core-induced oxidative stress and the antioxidant response to it was responsible for apoptosis changes. Methods. HCV core protein was expressed under control of the Tet-Off promoter in Huh-7 cells and HeLa cells. We chose to use deoxycholic acid (DCA) as a model because it is known to produce both reactive oxygen species (ROS) and apoptosis. Results. Core expression uniformly increased ROS and 8-hydroxy- 2′-deoxyguanosine (8-OHdG) under basal and DCAstimulated conditions. Core protein expression also increased manganese superoxide dismutase levels. Core protein inhibited DCA-mediated mitochondrial membrane depolarization and DCA-mediated activation of caspase-9 and caspase-3, despite the increase in ROS by DCA. Core protein inhibited DCA-mediated apoptosis by increasing Bcl-xL protein and decreasing Bax protein, without affecting the proportion of Bax between mitochondria and cytosol, resulting in suppression of cytochrome c release from mitochondria into cytoplasm. Conclusions. HCV core protein induces oxidative DNA damage, whereas it inhibits apoptosis that is accompanied by enhancement of ROS production. Thus, oxidative stress and apoptosis modulation by core protein are independent of each other.",
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AU - Hara, Yuichi

AU - Hino, Keisuke

AU - Okuda, Michiari

AU - Furutani, Takakazu

AU - Hidaka, Isao

AU - Yamaguchi, Yuhki

AU - Korenaga, Masaaki

AU - Li, Kui

AU - Weinman, Steven A.

AU - Lemon, Stanley M.

AU - Okita, Kiwamu

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N2 - Background. Hepatitis C virus (HCV) core protein is known to cause oxidative stress and alter apoptosis pathways. However, the apoptosis results are inconsistent, and the real significance of oxidative stress is not well known. The aim of this study was twofold. First, we wanted to confirm whether core-induced oxidative stress was really significant enough to cause DNA damage, and whether it induced cellular antioxidant responses. Second, we wanted to evaluate whether this core-induced oxidative stress and the antioxidant response to it was responsible for apoptosis changes. Methods. HCV core protein was expressed under control of the Tet-Off promoter in Huh-7 cells and HeLa cells. We chose to use deoxycholic acid (DCA) as a model because it is known to produce both reactive oxygen species (ROS) and apoptosis. Results. Core expression uniformly increased ROS and 8-hydroxy- 2′-deoxyguanosine (8-OHdG) under basal and DCAstimulated conditions. Core protein expression also increased manganese superoxide dismutase levels. Core protein inhibited DCA-mediated mitochondrial membrane depolarization and DCA-mediated activation of caspase-9 and caspase-3, despite the increase in ROS by DCA. Core protein inhibited DCA-mediated apoptosis by increasing Bcl-xL protein and decreasing Bax protein, without affecting the proportion of Bax between mitochondria and cytosol, resulting in suppression of cytochrome c release from mitochondria into cytoplasm. Conclusions. HCV core protein induces oxidative DNA damage, whereas it inhibits apoptosis that is accompanied by enhancement of ROS production. Thus, oxidative stress and apoptosis modulation by core protein are independent of each other.

AB - Background. Hepatitis C virus (HCV) core protein is known to cause oxidative stress and alter apoptosis pathways. However, the apoptosis results are inconsistent, and the real significance of oxidative stress is not well known. The aim of this study was twofold. First, we wanted to confirm whether core-induced oxidative stress was really significant enough to cause DNA damage, and whether it induced cellular antioxidant responses. Second, we wanted to evaluate whether this core-induced oxidative stress and the antioxidant response to it was responsible for apoptosis changes. Methods. HCV core protein was expressed under control of the Tet-Off promoter in Huh-7 cells and HeLa cells. We chose to use deoxycholic acid (DCA) as a model because it is known to produce both reactive oxygen species (ROS) and apoptosis. Results. Core expression uniformly increased ROS and 8-hydroxy- 2′-deoxyguanosine (8-OHdG) under basal and DCAstimulated conditions. Core protein expression also increased manganese superoxide dismutase levels. Core protein inhibited DCA-mediated mitochondrial membrane depolarization and DCA-mediated activation of caspase-9 and caspase-3, despite the increase in ROS by DCA. Core protein inhibited DCA-mediated apoptosis by increasing Bcl-xL protein and decreasing Bax protein, without affecting the proportion of Bax between mitochondria and cytosol, resulting in suppression of cytochrome c release from mitochondria into cytoplasm. Conclusions. HCV core protein induces oxidative DNA damage, whereas it inhibits apoptosis that is accompanied by enhancement of ROS production. Thus, oxidative stress and apoptosis modulation by core protein are independent of each other.

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