Malnutrition Impairs Interferon Signaling Through mTOR and FoxO Pathways in Patients With Chronic Hepatitis C

被引：51

作者：

Honda, Masao ^{[1
,2
]}

Takehana, Kenji ^{[3
]}

Sakai, Akito ^{[1
]}

Tagata, Yusuke ^{[3
]}

Shirasaki, Takayoshi ^{[2
]}

Nishitani, Shinobu ^{[3
]}

Muramatsu, Takahiko ^{[4
]}

Yamashita, Tatsuya ^{[1
]}

Nakamoto, Yasunari ^{[1
]}

Mizukoshi, Eishiro ^{[1
]}

Sakai, Yoshio ^{[1
]}

Yamashita, Taro ^{[1
]}

Nakamura, Mikiko ^{[1
]}

Shimakami, Tetsuro ^{[5
]}

Yi, Minkyung ^{[6
,7
]}

Lemon, Stanley M. ^{[5
]}

Suzuki, Tetsuo ^{[8
]}

Wakita, Takaji ^{[8
]}

Kaneko, Shuichi ^{[1
]}

机构：

[1] Kanazawa Univ, Grad Sch Med, Dept Gastroenterol, Kanazawa, Ishikawa 9208641, Japan

[2] Kanazawa Univ, Grad Sch Med, Dept Adv Med Technol, Kanazawa, Ishikawa 9208641, Japan

[3] Ajinomoto Pharmaceut Co Ltd, Res Ctr, Exploratory Res Labs, Kanazawa, Ishikawa, Japan

[4] Ajinomoto Co Inc, Inst Innovat, Frontier Res Labs, Kanagawa, Japan

[5] Univ N Carolina, Sch Med, Div Infect Dis, Chapel Hill, NC USA

[6] Univ Texas Med Branch, Inst Human Infect & Immun, Ctr Hepatitis Res, Galveston, TX USA

[7] Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX USA

[8] Natl Inst Infect Dis, Dept Virol 2, Tokyo, Japan

来源：

GASTROENTEROLOGY | 2011年 / 141卷 / 01期

关键词：

HCV; Liver Disease; Therapy; Diet; CHAIN AMINO-ACIDS; GENETIC-VARIATION; CELL-GROWTH; MYC; RIBAVIRIN; THERAPY; COMPLEX; TARGET; IL28B; ALPHA;

D O I：

10.1053/j.gastro.2011.03.051

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

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.

引用

页码：128 / U211

页数：15

共 20 条

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