Endoplasmic Reticulum Stress Links Hepatitis C Virus RNA Replication to Wild-Type PGC-1α/Liver-Specific PGC-1α Upregulation

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 alpha) 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 alpha(L-PGC-1 alpha) transcript, which is proposed to reflect human adaption to more complex pathways. However, the effect of HCV infection on L-PGC-1 alpha expression and the mechanism by which HCV modulates WT-PGC-1 alpha/L-PGC-1 alpha remain unclear. In this study, we showed that HCV infection upregulated both WT-PGC-1 alpha and L-PGC-1 alpha, which further promoted HCV production. The upregulation of both PGC-1 alpha 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 alpha was mediated by the phosphorylation of cyclic AMP(cAMP)-responsive element-binding protein (CREB), whereas that of L-PGC-1 alpha 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-PGC1 alpha/L-PGC-1 alpha and phosphorylated CREB. In contrast, pharmacological inhibition of HCV-induced ER stress impaired WT-PGC-1 alpha/L-PGC-1 alpha upregulation along with decreased phosphorylated CREB. The correlation of hepatic mPGC-1 alpha with ER stress was further confirmed in mice. Overall, HCV infection upregulates both WT-PGC-1 alpha and L-PGC-1 alpha through an ER stress-mediated, phosphorylated CREB-dependent pathway, and both PGC-1 alpha isoforms promote HCV production in turn. IMPORTANCE 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 alpha (WT-PGC-1 alpha, has recently been demonstrated to link HCV infection to hepatic IR. A recent study has characterized a novel human liver-specific PGC-1 alpha(L-PGC-1 alpha), which reflects human adaption to more complex pathways. However, the effect of HCV infection on L-PGC-1 alpha expression and the mechanism by which HCV regulates WT-PGC-1 alpha/L-PGC-1 alpha remain unclear. In this study, we showed that HCV infection upregulated both WT-PGC-1 alpha and L-PGC-1 alpha, which further promoted HCV production. WT-PGC-1 alpha upregulation was mediated by CREB phosphorylation, whereas L-PGC-1 alpha upregulation was mediated by CREB phosphorylation and FoxO1 dephosphorylation. HCV-induced ER stress mediated WT-PGC-1 alpha/L-PGC-1 alpha upregulation and CREB phosphorylation. Overall, this study provides new insights into the mechanism by which HCV upregulates WT-PGC-1 alpha/L-PGC-1 alpha and highlights the novel intervention of HCV-ER stress-PGC-1 alpha signaling for HCV therapy and HCV-induced IR therapy.