Hepatitis delta virus-induced IFN-beta production alters metabolic phenotype of hepatocytes

Hepatitis delta virus (HDV), a satellite of hepatitis B virus (HBV), aggravates HBV-mediated liver disease. To understand the underlying pathological processes, the interplay between HDV and hepatocyte metabolism was studied. Transcriptome and isotope tracing of differentiated, HDV-infected hepatocytes showed increased serine, asparagine and glutathione synthesis, but reduced TCA cycle and respiratory activity and in particular blocked spare respiratory capacity. HDV-induced IFN-beta was found to drive many of the observed changes, in part by activation of ATF4 by yet unidentified mechanisms. The impact of IFN-beta on liver metabolism, so far ill explored, was further studied. IFN-beta was cytoprotective by mediating resistance to oxidants, but reduced expression of liver differentiation markers, thus potentially playing an important role in HDV-associated liver pathology. Given the poor efficacy of IFN for HDV patient treatment, this discovery opens the question whether the cytoprotective and metabolic effects of this cytokine are beneficial for patients.