ABSTRACT: Hepatitis C virus (HCV) causes not only severe liver problems but also extrahepatic manifestations, such as insulin resistance (IR). Wild-type peroxisome proliferator-activated receptor gamma coactivator 1 alpha (WT-PGC-1?) is essential in hepatic gluconeogenesis and has recently been demonstrated to link HCV infection to hepatic insulin resistance (IR). A recent study has characterized a novel human liver-specific PGC-1? (L-PGC-1?) transcript, which is proposed to reflect human adaption to more complex pathways. However, the effect of HCV infection on L-PGC-1? expression and the mechanism by which HCV modulates WT-PGC-1?/L-PGC-1? remain unclear. In this study, we showed that HCV infection upregulated both WT-PGC-1? and L-PGC-1?, which further promoted HCV production. The upregulation of both PGC-1? isoforms depended on HCV RNA replication. By using promoter-luciferase reporters, kinase inhibitors, and dominant negative mutants, we further observed that the HCV-induced upregulation of WT-PGC-1? was mediated by the phosphorylation of cyclic AMP (cAMP)-responsive element-binding protein (CREB), whereas that of L-PGC-1? was mediated by CREB phosphorylation and forkhead box O1 dephosphorylation. Moreover, HCV infection induced endoplasmic reticulum (ER) stress, and pharmacological induction of ER stress upregulated WT-PGC-1?/L-PGC-1? and phosphorylated CREB. In contrast, pharmacological inhibition of HCV-induced ER stress impaired WT-PGC-1?/L-PGC-1? upregulation along with decreased phosphorylated CREB. The correlation of hepatic mPGC-1? with ER stress was further confirmed in mice. Overall, HCV infection upregulates both WT-PGC-1? and L-PGC-1? through an ER stress-mediated, phosphorylated CREB-dependent pathway, and both PGC-1? isoforms promote HCV production in turn.HCV causes not only severe liver problems but also extrahepatic manifestations, such as insulin resistance (IR). As a key regulator in energy metabolism, wild-type PGC-1? (WT-PGC-1?), has recently been demonstrated to link HCV infection to hepatic IR. A recent study has characterized a novel human liver-specific PGC-1? (L-PGC-1?), which reflects human adaption to more complex pathways. However, the effect of HCV infection on L-PGC-1? expression and the mechanism by which HCV regulates WT-PGC-1?/L-PGC-1? remain unclear. In this study, we showed that HCV infection upregulated both WT-PGC-1? and L-PGC-1?, which further promoted HCV production. WT-PGC-1? upregulation was mediated by CREB phosphorylation, whereas L-PGC-1? upregulation was mediated by CREB phosphorylation and FoxO1 dephosphorylation. HCV-induced ER stress mediated WT-PGC-1?/L-PGC-1? upregulation and CREB phosphorylation. Overall, this study provides new insights into the mechanism by which HCV upregulates WT-PGC-1?/L-PGC-1? and highlights the novel intervention of HCV-ER stress-PGC-1? signaling for HCV therapy and HCV-induced IR therapy.
