title: Malnutrition impairs interferon signaling through mTOR and FoxO pathways in patients with chronic hepatitis C.
abstract: OBJECTIVE
  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.
authors: Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
authors: Masao
authors: M
authors: Honda
authors: Kenji
authors: K
authors: Takehana
authors: Akito
authors: A
authors: Sakai
authors: Yusuke
authors: Y
authors: Tagata
authors: Takayoshi
authors: T
authors: Shirasaki
authors: Shinobu
authors: S
authors: Nishitani
authors: Takahiko
authors: T
authors: Muramatsu
authors: Tatsuya
authors: T
authors: Yamashita
authors: Yasunari
authors: Y
authors: Nakamoto
authors: Eishiro
authors: E
authors: Mizukoshi
authors: Yoshio
authors: Y
authors: Sakai
authors: Taro
authors: T
authors: Yamashita
authors: Mikiko
authors: M
authors: Nakamura
authors: Tetsuro
authors: T
authors: Shimakami
authors: Minkyung
authors: M
authors: Yi
authors: Stanley M
authors: SM
authors: Lemon
authors: Tetsuo
authors: T
authors: Suzuki
authors: Takaji
authors: T
authors: Wakita
authors: Shuichi
authors: S
authors: Kaneko
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use*; D001483:Base Sequence; D045744:Cell Line, Tumor; D004359:Drug Therapy, Combination; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics / Q000254:growth & development; D019698:Hepatitis C, Chronic / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use*; D007372:Interferons; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D007564:Japan; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000821:virology; D008103:Liver Cirrhosis / Q000378:metabolism / Q000821:virology; D008297:Male; D044342:Malnutrition / Q000378:metabolism* / Q000821:virology; D000076222:Mechanistic Target of Rapamycin Complex 1; D008875:Middle Aged; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes; D009752:Nutritional Status; D016017:Odds Ratio; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D011110:Polymorphism, Genetic; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D012367:RNA, Viral / Q000097:blood; D011994:Recombinant Proteins; D012044:Regression Analysis; D012254:Ribavirin / Q000627:therapeutic use; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000637:Transaminases / Q000378:metabolism; D014162:Transfection; D016896:Treatment Outcome; D019562:Viral Load; D014779:Virus Replication / Q000187:drug effects; D000095022:Interferon Lambda
chemical_list: D000998:Antiviral Agents; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D011092:Polyethylene Glycols; D011506:Proteins; D012367:RNA, Viral; D011994:Recombinant Proteins; D012254:Ribavirin; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D058570:TOR Serine-Threonine Kinases; D000637:Transaminases; C499517:FOXO3 protein, human; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C106644:SOCS3 protein, human; C490590:BCAT1 protein, human; C546842:MTOR protein, human; C417083:peginterferon alfa-2b