BACKGROUND & AIMS: The metabolic identity of a hepatocyte is determined by its position along the porto-centrilobular axis of a liver lobule. Altered patterns of metabolic liver zonation are associated with several pathologies. In hepatitis C, although only a minority of hepatocytes harbour the virus, the liver undergoes major systemic metabolic changes. We have investigated the HCV-driven mechanisms that allow the systemic loss of metabolic zonation. METHODS: Transgenic mice with hepatocyte-targeted expression of all HCV proteins (FL-N/35 model) and needle biopsies from hepatitis C patients were studied with respect to patterns of lipid deposition in the context of metabolic zonation of the liver lobule. RESULTS: We report that low levels of viral proteins are sufficient to drive striking alterations of hepatic metabolic zonation. In mice, a major lipogenic enzyme, fatty acid synthase, was redistributed from its normal periportal expression into the midzone of the lobule, coinciding with a highly specific midzone accumulation of lipids. Strikingly, alteration of zonation was not limited to lipogenic enzymes and appeared to be driven by systemic signalling via the Wnt/β-catenin pathway. Importantly, we show that similarly perturbed metabolic zonation appears to precede steatosis in early stages of human disease associated with HCV infection. CONCLUSIONS: Our results rationalize systemic effects on liver metabolism, triggered by a minority of infected cells, thus opening new perspectives for the investigation of HCV-related pathologies.