Malnutrition impairs interferon signaling through mTOR and FoxO pathways in patients with chronic hepatitis C

Masao Honda, Kenji Takehana, Akito Sakai, Yusuke Tagata, Takayoshi Shirasaki, Shinobu Nishitani, Takahiko Muramatsu, Tatsuya Yamashita, Yasunari Nakamoto, Eishiro Mizukoshi, Yoshio Sakai, Taro Yamashita, Mikiko Nakamura, Tetsuro Shimakami, Min Kyung Yi, Stanley M. Lemon, Tetsuo Suzuki, Takaji Wakita, Shuichi Kaneko

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Abstract

Background & Aims: Patients with advanced chronic hepatitis C (CH-C) often are malnourished, but the effects of malnutrition on interferon (IFN) signaling and response to treatment have not been determined. We assessed the importance of the nutritional state of the liver on IFN signaling and treatment response. Methods: We studied data from 168 patients with CH-C who were treated with the combination of pegylated-IFN and ribavirin. Plasma concentrations of amino acids were measured by mass spectrometry. Liver gene expression profiles were obtained from 91 patients. Huh-7 cells were used to evaluate the IFN signaling pathway, mammalian target of rapamycin complex 1 (mTORC1), and forkhead box O (FoxO). Antiviral signaling induced by branched-chain amino acids (BCAAs) was determined using the in vitro hepatitis C virus replication system. Results: Multivariate logistic regression analysis showed that Fischer's ratio was associated significantly with nonresponders, independent of interleukin-28B polymorphisms or the histologic stage of the liver. Fischer's ratio was correlated inversely with the expression of BCAA transaminase 1, and was affected by hepatic mTORC1 signaling. IFN stimulation was impaired substantially in Huh-7 cells grown in medium that was low in amino acid concentration, through repressed mTORC1 signaling, and increased Socs3 expression, which was regulated by Foxo3a. BCAA could restore impaired IFN signaling and inhibit hepatitis C virus replication under conditions of malnutrition. Conclusions: Malnutrition impaired IFN signaling by inhibiting mTORC1 and activating Socs3 signaling through Foxo3a. Increasing BCAAs to up-regulate IFN signaling might be used as a new therapeutic approach for patients with advanced CH-C.

Original languageEnglish (US)
JournalGastroenterology
Volume141
Issue number1
DOIs
StatePublished - Jul 2011

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Chronic Hepatitis C
Malnutrition
Interferons
Branched Chain Amino Acids
Liver
Virus Replication
Hepacivirus
Amino Acids
Ribavirin
Interleukins
Transcriptome
Antiviral Agents
Mass Spectrometry
Up-Regulation
Therapeutics
Logistic Models
Regression Analysis
mechanistic target of rapamycin complex 1

Keywords

  • Diet
  • HCV
  • Liver Disease
  • Therapy

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Honda, M., Takehana, K., Sakai, A., Tagata, Y., Shirasaki, T., Nishitani, S., ... Kaneko, S. (2011). Malnutrition impairs interferon signaling through mTOR and FoxO pathways in patients with chronic hepatitis C. Gastroenterology, 141(1). https://doi.org/10.1053/j.gastro.2011.03.051

Malnutrition impairs interferon signaling through mTOR and FoxO pathways in patients with chronic hepatitis C. / Honda, Masao; Takehana, Kenji; Sakai, Akito; Tagata, Yusuke; Shirasaki, Takayoshi; Nishitani, Shinobu; Muramatsu, Takahiko; Yamashita, Tatsuya; Nakamoto, Yasunari; Mizukoshi, Eishiro; Sakai, Yoshio; Yamashita, Taro; Nakamura, Mikiko; Shimakami, Tetsuro; Yi, Min Kyung; Lemon, Stanley M.; Suzuki, Tetsuo; Wakita, Takaji; Kaneko, Shuichi.

In: Gastroenterology, Vol. 141, No. 1, 07.2011.

Research output: Contribution to journalArticle

Honda, M, Takehana, K, Sakai, A, Tagata, Y, Shirasaki, T, Nishitani, S, Muramatsu, T, Yamashita, T, Nakamoto, Y, Mizukoshi, E, Sakai, Y, Yamashita, T, Nakamura, M, Shimakami, T, Yi, MK, Lemon, SM, Suzuki, T, Wakita, T & Kaneko, S 2011, 'Malnutrition impairs interferon signaling through mTOR and FoxO pathways in patients with chronic hepatitis C', Gastroenterology, vol. 141, no. 1. https://doi.org/10.1053/j.gastro.2011.03.051
Honda, Masao ; Takehana, Kenji ; Sakai, Akito ; Tagata, Yusuke ; Shirasaki, Takayoshi ; Nishitani, Shinobu ; Muramatsu, Takahiko ; Yamashita, Tatsuya ; Nakamoto, Yasunari ; Mizukoshi, Eishiro ; Sakai, Yoshio ; Yamashita, Taro ; Nakamura, Mikiko ; Shimakami, Tetsuro ; Yi, Min Kyung ; Lemon, Stanley M. ; Suzuki, Tetsuo ; Wakita, Takaji ; Kaneko, Shuichi. / Malnutrition impairs interferon signaling through mTOR and FoxO pathways in patients with chronic hepatitis C. In: Gastroenterology. 2011 ; Vol. 141, No. 1.
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abstract = "Background & Aims: Patients with advanced chronic hepatitis C (CH-C) often are malnourished, but the effects of malnutrition on interferon (IFN) signaling and response to treatment have not been determined. We assessed the importance of the nutritional state of the liver on IFN signaling and treatment response. Methods: We studied data from 168 patients with CH-C who were treated with the combination of pegylated-IFN and ribavirin. Plasma concentrations of amino acids were measured by mass spectrometry. Liver gene expression profiles were obtained from 91 patients. Huh-7 cells were used to evaluate the IFN signaling pathway, mammalian target of rapamycin complex 1 (mTORC1), and forkhead box O (FoxO). Antiviral signaling induced by branched-chain amino acids (BCAAs) was determined using the in vitro hepatitis C virus replication system. Results: Multivariate logistic regression analysis showed that Fischer's ratio was associated significantly with nonresponders, independent of interleukin-28B polymorphisms or the histologic stage of the liver. Fischer's ratio was correlated inversely with the expression of BCAA transaminase 1, and was affected by hepatic mTORC1 signaling. IFN stimulation was impaired substantially in Huh-7 cells grown in medium that was low in amino acid concentration, through repressed mTORC1 signaling, and increased Socs3 expression, which was regulated by Foxo3a. BCAA could restore impaired IFN signaling and inhibit hepatitis C virus replication under conditions of malnutrition. Conclusions: Malnutrition impaired IFN signaling by inhibiting mTORC1 and activating Socs3 signaling through Foxo3a. Increasing BCAAs to up-regulate IFN signaling might be used as a new therapeutic approach for patients with advanced CH-C.",
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AU - Honda, Masao

AU - Takehana, Kenji

AU - Sakai, Akito

AU - Tagata, Yusuke

AU - Shirasaki, Takayoshi

AU - Nishitani, Shinobu

AU - Muramatsu, Takahiko

AU - Yamashita, Tatsuya

AU - Nakamoto, Yasunari

AU - Mizukoshi, Eishiro

AU - Sakai, Yoshio

AU - Yamashita, Taro

AU - Nakamura, Mikiko

AU - Shimakami, Tetsuro

AU - Yi, Min Kyung

AU - Lemon, Stanley M.

AU - Suzuki, Tetsuo

AU - Wakita, Takaji

AU - Kaneko, Shuichi

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N2 - Background & Aims: Patients with advanced chronic hepatitis C (CH-C) often are malnourished, but the effects of malnutrition on interferon (IFN) signaling and response to treatment have not been determined. We assessed the importance of the nutritional state of the liver on IFN signaling and treatment response. Methods: We studied data from 168 patients with CH-C who were treated with the combination of pegylated-IFN and ribavirin. Plasma concentrations of amino acids were measured by mass spectrometry. Liver gene expression profiles were obtained from 91 patients. Huh-7 cells were used to evaluate the IFN signaling pathway, mammalian target of rapamycin complex 1 (mTORC1), and forkhead box O (FoxO). Antiviral signaling induced by branched-chain amino acids (BCAAs) was determined using the in vitro hepatitis C virus replication system. Results: Multivariate logistic regression analysis showed that Fischer's ratio was associated significantly with nonresponders, independent of interleukin-28B polymorphisms or the histologic stage of the liver. Fischer's ratio was correlated inversely with the expression of BCAA transaminase 1, and was affected by hepatic mTORC1 signaling. IFN stimulation was impaired substantially in Huh-7 cells grown in medium that was low in amino acid concentration, through repressed mTORC1 signaling, and increased Socs3 expression, which was regulated by Foxo3a. BCAA could restore impaired IFN signaling and inhibit hepatitis C virus replication under conditions of malnutrition. Conclusions: Malnutrition impaired IFN signaling by inhibiting mTORC1 and activating Socs3 signaling through Foxo3a. Increasing BCAAs to up-regulate IFN signaling might be used as a new therapeutic approach for patients with advanced CH-C.

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KW - Diet

KW - HCV

KW - Liver Disease

KW - Therapy

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