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-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.


OBJECTIVE
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-1α (WT-PGC-1α), has recently been demonstrated to link HCV infection to hepatic IR. A recent study has characterized a novel human liver-specific PGC-1α (L-PGC-1α), which reflects human adaption to more complex pathways. However, the effect of HCV infection on L-PGC-1α expression and the mechanism by which HCV regulates 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. WT-PGC-1α upregulation was mediated by CREB phosphorylation, whereas L-PGC-1α upregulation was mediated by CREB phosphorylation and FoxO1 dephosphorylation. HCV-induced ER stress mediated WT-PGC-1α/L-PGC-1α upregulation and CREB phosphorylation. Overall, this study provides new insights into the mechanism by which HCV upregulates WT-PGC-1α/L-PGC-1α and highlights the novel intervention of HCV-ER stress-PGC-1α signaling for HCV therapy and HCV-induced IR therapy.
Laboratory of Viral Immunology, State key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China Sino-French Hoffmann Institute of Immunology, Guangzhou Medical University, Guangzhou, China.
Wenxia
W
Yao
Laboratory of Viral Immunology, State key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China Sino-French Hoffmann Institute of Immunology, Guangzhou Medical University, Guangzhou, China.
Hua
H
Cai
Sino-French Hoffmann Institute of Immunology, Guangzhou Medical University, Guangzhou, China.
Xinlei
X
Li
Laboratory of Viral Immunology, State key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
Ting
T
Li
Laboratory of Viral Immunology, State key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
Longbo
L
Hu
Laboratory of Viral Immunology, State key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China Sino-French Hoffmann Institute of Immunology, Guangzhou Medical University, Guangzhou, China pengtao@gzhmu.edu.cn.
Tao
T
Peng
D000818:Animals; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D016174:Hepacivirus / Q000502:physiology*; D022781:Hepatocytes / Q000821:virology*; D006801:Humans; D008099:Liver / Q000821:virology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D020033:Protein Isoforms / Q000096:biosynthesis; D014157:Transcription Factors / Q000096:biosynthesis*; D015854:Up-Regulation; D014779:Virus Replication
C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D020033:Protein Isoforms; D014157:Transcription Factors