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| Content Provider | PubMed Central |
|---|---|
| Author | Yao, Wenxia Cai, Hua Li, Xinlei Ting, Li Hu, Longbo Peng, Tao |
| Editor | Diamond, M. S. |
| Copyright Year | 2014 |
| 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-1α) 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-1α (L-PGC-1α) transcript, which is proposed to reflect human adaption to more complex pathways. However, the effect of HCV infection on L-PGC-1α expression and the mechanism by which HCV modulates WT-PGC-1α/L-PGC-1α remain unclear. In this study, we showed that HCV infection upregulated both WT-PGC-1α and L-PGC-1α, which further promoted HCV production. The upregulation of both PGC-1α 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-1α was mediated by the phosphorylation of cyclic AMP (cAMP)-responsive element-binding protein (CREB), whereas that of L-PGC-1α 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-1α/L-PGC-1α and phosphorylated CREB. In contrast, pharmacological inhibition of HCV-induced ER stress impaired WT-PGC-1α/L-PGC-1α upregulation along with decreased phosphorylated CREB. The correlation of hepatic mPGC-1α with ER stress was further confirmed in mice. Overall, HCV infection upregulates both WT-PGC-1α and L-PGC-1α through an ER stress-mediated, phosphorylated CREB-dependent pathway, and both PGC-1α isoforms promote HCV production in turn. |
| Related Links | http://dx.doi.org/10.1128/jvi.01202-14 |
| Ending Page | 8374 |
| Page Count | 14 |
| Starting Page | 8361 |
| File Format | |
| ISSN | 0022538X |
| e-ISSN | 10985514 |
| Journal | Journal of Virology |
| Issue Number | 15 |
| Volume Number | 88 |
| Language | English |
| Publisher | American Society for Microbiology |
| Publisher Date | 2014-08-01 |
| Access Restriction | Open |
| Rights Holder | American Society for Microbiology |
| Subject Keyword | Immunology Virology Research in Higher Education |
| Content Type | Text |
| Resource Type | Article |
| Subject | Virology Immunology Microbiology Insect Science |
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