HBx, and essential factor for HBV replication, can induce fatty liver by the induction of SREBP1c and PPARγ as well as LXR.147,148 This has led to the term “metaboloviruses” for hepatitis B (and C virus).149 In line with this concept, also PGC-1α, a major metabolic regulator and coactivator of key gluconeogenic CH5424802 genes, robustly activates
HBV transcription. Short-term fasting, which activates gluconeogenesis by way of PGC-1α, also markedly induces HBV gene expression. Notably, this induction is completely reversible by refeeding, indicating that nutritional signals may impact HBV replication.150 Serum bile acids have been recently described as prognostic markers predicting failure to reach sustained clearance of HCV in response to antiviral therapy.151 Physiological concentrations of bile acids up-regulate genotype 1 HCV RNA replication by way of FXR (Supporting Table 6). In vitro, FXR silencing and antagonism by guggulsterone blocks the induction of viral replication by bile acids.143 Moreover,
bile acids reduce the anti-HCV effect of interferon in vitro.152 These findings suggest that FXR antagonism or bile acid sequestrants could be used to support antiviral therapy in patients with high bile acid levels. HCV infection is accompanied by hepatic steatosis (“metabolovirus”) especially in patients infected with genotype 3, who have lower hepatic expression levels of PPARα in comparison with nongenotype 3 patients.153 Similar to the HBx protein of HBV, the HCV core protein also induces LXR, SREBP1c, see more and PPARγ activity, thereby stimulating lipogenesis in liver154,155 (Fig. 2; Supporting Table 6). The HCV nonstructural protein NS5A increases recruitment of the transcriptional coactivator PGC-1α, further augmenting PPARγ-induced lipid accumulation.156 Preliminary human data
suggest beneficial effects of PPARα and PPARγ agonists on viral load and liver enzymes when continued with current treatment regimens.157,158 These results suggest that PPARs may represent new therapeutic targets combating HCV infection. In line with this, it should, however, be noted that persistent activation of PPARα by the HCV core protein has been linked PLEKHB2 to hepatocarcinogenesis in mice159 (Supporting Table 6). Notably, progression and therapeutic response have been linked to vitamin D serum levels, pointing towards a potential role of VDR.160,161 Bile acids have been identified as one of the key mitogens that are able to drive liver regeneration, when the remaining hepatocytes are exposed to an increased bile acid load.162 The importance of bile acids and bile acid-mediated FXR-dependent pathways for liver regeneration is underlined by the observation, that absence of bile acids (or a bile acid-derived factor) in the intestine (e.g., by way of external biliary drainage, biliary obstruction) delays liver regeneration.163 Moreover, mice lacking FXR have delayed and impaired liver regeneration after partial hepatectomy.