Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
Gastroenterology. 2011 Jul;141(1):128-40, 140.e1-2. doi: 10.1053/j.gastro.2011.03.051. Epub 2011 Mar 31.
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.
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.
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.
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.
患有晚期慢性丙型肝炎（CH-C）的患者常伴有营养不良，但营养不良对干扰素（IFN）信号转导和治疗反应的影响尚未确定。我们评估了肝脏营养状态对 IFN 信号转导和治疗反应的重要性。
我们研究了 168 例接受聚乙二醇干扰素和利巴韦林联合治疗的 CH-C 患者的数据。采用质谱法测定血浆氨基酸浓度。从 91 例患者中获得肝基因表达谱。用 Huh-7 细胞评估 IFN 信号通路、雷帕霉素复合物 1（mTORC1）和叉头框 O（FoxO）。通过体外丙型肝炎病毒复制系统测定支链氨基酸（BCAAs）诱导的抗病毒信号。
多变量逻辑回归分析表明，Fischer 比与无应答者显著相关，独立于白细胞介素 28B 多态性或肝组织学分期。Fischer 比与 BCAA 转氨酶 1 的表达呈负相关，受肝 mTORC1 信号的影响。在氨基酸浓度低的培养基中生长的 Huh-7 细胞中，IFN 刺激受到显著抑制，通过抑制 mTORC1 信号和增加由 Foxo3a 调节的 Socs3 表达。BCAA 可在营养不良条件下恢复受损的 IFN 信号转导并抑制丙型肝炎病毒复制。
营养不良通过抑制 mTORC1 和通过 Foxo3a 激活 Socs3 信号转导来损害 IFN 信号转导。增加 BCAA 以上调 IFN 信号转导可能是治疗晚期 CH-C 患者的新方法。
