Hepatitis C virus infection promotes hepatic gluconeogenesis through an NS5A-mediated, FoxO1-dependent pathway

Lin Deng, Ikuo Shoji, Wataru Ogawa, Shusaku Kaneda, Tomoyoshi Soga, Da Peng Jiang, Yoshi Hiro Ide, Hak Hottal

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

Chronic hepatitis C virus (HCV) infection is often associated with type 2 diabetes. However, the precise mechanism underlying this association is still unclear. Here, using Huh-7.5 cells either harboring HCV-1b RNA replicons or infected with HCV-2a, we showed that HCV transcriptionally upregulated the genes for phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase), the rate-limiting enzymes for hepatic gluconeogenesis. In this way, HCV enhanced the cellular production of glucose 6-phosphate (G6P) and glucose. PEPCK and G6Pase gene expressions are controlled by the transcription factor forkhead box O1 (FoxO1). We observed that although neither the mRNA levels nor the protein levels of FoxO1 expression were affected by HCV, the level of phosphorylation of FoxO1 at Ser319 was markedly diminished in HCV-infected cells compared to the control cells, resulting in an increased nuclear accumulation of FoxO1, which is essential for sustaining its transcriptional activity. It was unlikely that the decreased level of FoxO1 phosphorylation was mediated through Akt inactivation, as we observed an increased phosphorylation of Akt at Ser473 in HCVinfected cells compared to control cells. By using specific inhibitors of c-Jun N-terminal kinase (JNK) and reactive oxygen species (ROS), we demonstrated that HCV infection induced JNK activation via increased mitochondrial ROS production, resulting in decreased FoxO1 phosphorylation, FoxO1 nuclear accumulation, and, eventually, increased glucose production. We also found that HCV NS5A mediated increased ROS production and JNK activation, which is directly linked with the FoxO1-dependent increased gluconeogenesis. Taken together, these observations suggest that HCV promotes hepatic gluconeogenesis through an NS5Amediated, FoxO1-dependent pathway.

Original languageEnglish
Pages (from-to)8556-8568
Number of pages13
JournalJournal of Virology
Volume85
Issue number17
DOIs
Publication statusPublished - 2011 Sep

Fingerprint

Hepatitis C virus
Gluconeogenesis
gluconeogenesis
Virus Diseases
Hepacivirus
liver
Liver
infection
phosphorylation
Phosphorylation
glucose-6-phosphatase
reactive oxygen species
Reactive Oxygen Species
Glucose-6-Phosphatase
Phosphoenolpyruvate
cells
phosphotransferases (kinases)
Phosphotransferases
chronic hepatitis C
Forkhead Transcription Factors

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Hepatitis C virus infection promotes hepatic gluconeogenesis through an NS5A-mediated, FoxO1-dependent pathway. / Deng, Lin; Shoji, Ikuo; Ogawa, Wataru; Kaneda, Shusaku; Soga, Tomoyoshi; Jiang, Da Peng; Ide, Yoshi Hiro; Hottal, Hak.

In: Journal of Virology, Vol. 85, No. 17, 09.2011, p. 8556-8568.

Research output: Contribution to journalArticle

Deng, Lin ; Shoji, Ikuo ; Ogawa, Wataru ; Kaneda, Shusaku ; Soga, Tomoyoshi ; Jiang, Da Peng ; Ide, Yoshi Hiro ; Hottal, Hak. / Hepatitis C virus infection promotes hepatic gluconeogenesis through an NS5A-mediated, FoxO1-dependent pathway. In: Journal of Virology. 2011 ; Vol. 85, No. 17. pp. 8556-8568.
@article{5269c436099f480eabc25d16f62941b4,
title = "Hepatitis C virus infection promotes hepatic gluconeogenesis through an NS5A-mediated, FoxO1-dependent pathway",
abstract = "Chronic hepatitis C virus (HCV) infection is often associated with type 2 diabetes. However, the precise mechanism underlying this association is still unclear. Here, using Huh-7.5 cells either harboring HCV-1b RNA replicons or infected with HCV-2a, we showed that HCV transcriptionally upregulated the genes for phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase), the rate-limiting enzymes for hepatic gluconeogenesis. In this way, HCV enhanced the cellular production of glucose 6-phosphate (G6P) and glucose. PEPCK and G6Pase gene expressions are controlled by the transcription factor forkhead box O1 (FoxO1). We observed that although neither the mRNA levels nor the protein levels of FoxO1 expression were affected by HCV, the level of phosphorylation of FoxO1 at Ser319 was markedly diminished in HCV-infected cells compared to the control cells, resulting in an increased nuclear accumulation of FoxO1, which is essential for sustaining its transcriptional activity. It was unlikely that the decreased level of FoxO1 phosphorylation was mediated through Akt inactivation, as we observed an increased phosphorylation of Akt at Ser473 in HCVinfected cells compared to control cells. By using specific inhibitors of c-Jun N-terminal kinase (JNK) and reactive oxygen species (ROS), we demonstrated that HCV infection induced JNK activation via increased mitochondrial ROS production, resulting in decreased FoxO1 phosphorylation, FoxO1 nuclear accumulation, and, eventually, increased glucose production. We also found that HCV NS5A mediated increased ROS production and JNK activation, which is directly linked with the FoxO1-dependent increased gluconeogenesis. Taken together, these observations suggest that HCV promotes hepatic gluconeogenesis through an NS5Amediated, FoxO1-dependent pathway.",
author = "Lin Deng and Ikuo Shoji and Wataru Ogawa and Shusaku Kaneda and Tomoyoshi Soga and Jiang, {Da Peng} and Ide, {Yoshi Hiro} and Hak Hottal",
year = "2011",
month = "9",
doi = "10.1128/JVI.00146-11",
language = "English",
volume = "85",
pages = "8556--8568",
journal = "Journal of Virology",
issn = "0022-538X",
publisher = "American Society for Microbiology",
number = "17",

}

TY - JOUR

T1 - Hepatitis C virus infection promotes hepatic gluconeogenesis through an NS5A-mediated, FoxO1-dependent pathway

AU - Deng, Lin

AU - Shoji, Ikuo

AU - Ogawa, Wataru

AU - Kaneda, Shusaku

AU - Soga, Tomoyoshi

AU - Jiang, Da Peng

AU - Ide, Yoshi Hiro

AU - Hottal, Hak

PY - 2011/9

Y1 - 2011/9

N2 - Chronic hepatitis C virus (HCV) infection is often associated with type 2 diabetes. However, the precise mechanism underlying this association is still unclear. Here, using Huh-7.5 cells either harboring HCV-1b RNA replicons or infected with HCV-2a, we showed that HCV transcriptionally upregulated the genes for phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase), the rate-limiting enzymes for hepatic gluconeogenesis. In this way, HCV enhanced the cellular production of glucose 6-phosphate (G6P) and glucose. PEPCK and G6Pase gene expressions are controlled by the transcription factor forkhead box O1 (FoxO1). We observed that although neither the mRNA levels nor the protein levels of FoxO1 expression were affected by HCV, the level of phosphorylation of FoxO1 at Ser319 was markedly diminished in HCV-infected cells compared to the control cells, resulting in an increased nuclear accumulation of FoxO1, which is essential for sustaining its transcriptional activity. It was unlikely that the decreased level of FoxO1 phosphorylation was mediated through Akt inactivation, as we observed an increased phosphorylation of Akt at Ser473 in HCVinfected cells compared to control cells. By using specific inhibitors of c-Jun N-terminal kinase (JNK) and reactive oxygen species (ROS), we demonstrated that HCV infection induced JNK activation via increased mitochondrial ROS production, resulting in decreased FoxO1 phosphorylation, FoxO1 nuclear accumulation, and, eventually, increased glucose production. We also found that HCV NS5A mediated increased ROS production and JNK activation, which is directly linked with the FoxO1-dependent increased gluconeogenesis. Taken together, these observations suggest that HCV promotes hepatic gluconeogenesis through an NS5Amediated, FoxO1-dependent pathway.

AB - Chronic hepatitis C virus (HCV) infection is often associated with type 2 diabetes. However, the precise mechanism underlying this association is still unclear. Here, using Huh-7.5 cells either harboring HCV-1b RNA replicons or infected with HCV-2a, we showed that HCV transcriptionally upregulated the genes for phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase), the rate-limiting enzymes for hepatic gluconeogenesis. In this way, HCV enhanced the cellular production of glucose 6-phosphate (G6P) and glucose. PEPCK and G6Pase gene expressions are controlled by the transcription factor forkhead box O1 (FoxO1). We observed that although neither the mRNA levels nor the protein levels of FoxO1 expression were affected by HCV, the level of phosphorylation of FoxO1 at Ser319 was markedly diminished in HCV-infected cells compared to the control cells, resulting in an increased nuclear accumulation of FoxO1, which is essential for sustaining its transcriptional activity. It was unlikely that the decreased level of FoxO1 phosphorylation was mediated through Akt inactivation, as we observed an increased phosphorylation of Akt at Ser473 in HCVinfected cells compared to control cells. By using specific inhibitors of c-Jun N-terminal kinase (JNK) and reactive oxygen species (ROS), we demonstrated that HCV infection induced JNK activation via increased mitochondrial ROS production, resulting in decreased FoxO1 phosphorylation, FoxO1 nuclear accumulation, and, eventually, increased glucose production. We also found that HCV NS5A mediated increased ROS production and JNK activation, which is directly linked with the FoxO1-dependent increased gluconeogenesis. Taken together, these observations suggest that HCV promotes hepatic gluconeogenesis through an NS5Amediated, FoxO1-dependent pathway.

UR - http://www.scopus.com/inward/record.url?scp=80052290588&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80052290588&partnerID=8YFLogxK

U2 - 10.1128/JVI.00146-11

DO - 10.1128/JVI.00146-11

M3 - Article

VL - 85

SP - 8556

EP - 8568

JO - Journal of Virology

JF - Journal of Virology

SN - 0022-538X

IS - 17

ER -