Abstract

BACKGROUND & AIMS: Patients with advanced chronic hepatitis C (CH-C) are often 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 Peg-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 complex1 (mTORC1), and forkhead box O (Foxo). Antiviral signaling induced by branched-chain amino acids (BCAAs) was determined using the in vitro HCV replication system.

RESULTS: Multivariate logistic regression analysis showed that Fischer's ratio was significantly associated with non-responders, independent of IL28B polymorphisms or the histologic stage of the liver. Fischer's ratio was inversely correlated with expression of BCAA transaminase 1, and was affected by hepatic mTORC1 signaling. IFN stimulation was substantially impaired in Huh-7 cells grown in medium 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 upregulate IFN signaling might be used as a new therapeutic approach for patients with advanced CH-C.