Cargando…
Pyruvate dehydrogenase kinase regulates hepatitis C virus replication
During replication, hepatitis C virus (HCV) utilizes macromolecules produced by its host cell. This process requires host cellular metabolic reprogramming to favor elevated levels of aerobic glycolysis. Therefore, we evaluated whether pyruvate dehydrogenase kinase (PDK), a mitochondrial enzyme that...
Autores principales: | , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4965757/ https://www.ncbi.nlm.nih.gov/pubmed/27471054 http://dx.doi.org/10.1038/srep30846 |
_version_ | 1782445309588144128 |
---|---|
author | Jung, Gwon-Soo Jeon, Jae-Han Choi, Yeon-Kyung Jang, Se Young Park, Soo Young Kim, Sung-Woo Byun, Jun-Kyu Kim, Mi-Kyung Lee, Sungwoo Shin, Eui-Cheol Lee, In-Kyu Kang, Yu Na Park, Keun-Gyu |
author_facet | Jung, Gwon-Soo Jeon, Jae-Han Choi, Yeon-Kyung Jang, Se Young Park, Soo Young Kim, Sung-Woo Byun, Jun-Kyu Kim, Mi-Kyung Lee, Sungwoo Shin, Eui-Cheol Lee, In-Kyu Kang, Yu Na Park, Keun-Gyu |
author_sort | Jung, Gwon-Soo |
collection | PubMed |
description | During replication, hepatitis C virus (HCV) utilizes macromolecules produced by its host cell. This process requires host cellular metabolic reprogramming to favor elevated levels of aerobic glycolysis. Therefore, we evaluated whether pyruvate dehydrogenase kinase (PDK), a mitochondrial enzyme that promotes aerobic glycolysis, can regulate HCV replication. Levels of c-Myc, hypoxia-inducible factor-1α (HIF-1α), PDK1, PDK3, glucokinase, and serine biosynthetic enzymes were compared between HCV-infected and uninfected human liver and Huh-7.5 cells infected with or without HCV. Protein and mRNA expression of c-Myc, HIF-1α, and glycolytic enzymes were significantly higher in HCV-infected human liver and hepatocytes than in uninfected controls. This increase was accompanied by upregulation of serine biosynthetic enzymes, suggesting cellular metabolism was altered toward facilitated nucleotide synthesis essential for HCV replication. JQ1, a c-Myc inhibitor, and dichloroacetate (DCA), a PDK inhibitor, decreased the expression of glycolytic and serine synthetic enzymes in HCV-infected hepatocytes, resulting in suppressed viral replication. Furthermore, when co-administered with IFN-α or ribavirin, DCA further inhibited viral replication. In summary, HCV reprograms host cell metabolism to favor glycolysis and serine biosynthesis; this is mediated, at least in part, by increased PDK activity, which provides a surplus of nucleotide precursors. Therefore, blocking PDK activity might have therapeutic benefits against HCV replication. |
format | Online Article Text |
id | pubmed-4965757 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-49657572016-08-08 Pyruvate dehydrogenase kinase regulates hepatitis C virus replication Jung, Gwon-Soo Jeon, Jae-Han Choi, Yeon-Kyung Jang, Se Young Park, Soo Young Kim, Sung-Woo Byun, Jun-Kyu Kim, Mi-Kyung Lee, Sungwoo Shin, Eui-Cheol Lee, In-Kyu Kang, Yu Na Park, Keun-Gyu Sci Rep Article During replication, hepatitis C virus (HCV) utilizes macromolecules produced by its host cell. This process requires host cellular metabolic reprogramming to favor elevated levels of aerobic glycolysis. Therefore, we evaluated whether pyruvate dehydrogenase kinase (PDK), a mitochondrial enzyme that promotes aerobic glycolysis, can regulate HCV replication. Levels of c-Myc, hypoxia-inducible factor-1α (HIF-1α), PDK1, PDK3, glucokinase, and serine biosynthetic enzymes were compared between HCV-infected and uninfected human liver and Huh-7.5 cells infected with or without HCV. Protein and mRNA expression of c-Myc, HIF-1α, and glycolytic enzymes were significantly higher in HCV-infected human liver and hepatocytes than in uninfected controls. This increase was accompanied by upregulation of serine biosynthetic enzymes, suggesting cellular metabolism was altered toward facilitated nucleotide synthesis essential for HCV replication. JQ1, a c-Myc inhibitor, and dichloroacetate (DCA), a PDK inhibitor, decreased the expression of glycolytic and serine synthetic enzymes in HCV-infected hepatocytes, resulting in suppressed viral replication. Furthermore, when co-administered with IFN-α or ribavirin, DCA further inhibited viral replication. In summary, HCV reprograms host cell metabolism to favor glycolysis and serine biosynthesis; this is mediated, at least in part, by increased PDK activity, which provides a surplus of nucleotide precursors. Therefore, blocking PDK activity might have therapeutic benefits against HCV replication. Nature Publishing Group 2016-07-29 /pmc/articles/PMC4965757/ /pubmed/27471054 http://dx.doi.org/10.1038/srep30846 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Jung, Gwon-Soo Jeon, Jae-Han Choi, Yeon-Kyung Jang, Se Young Park, Soo Young Kim, Sung-Woo Byun, Jun-Kyu Kim, Mi-Kyung Lee, Sungwoo Shin, Eui-Cheol Lee, In-Kyu Kang, Yu Na Park, Keun-Gyu Pyruvate dehydrogenase kinase regulates hepatitis C virus replication |
title | Pyruvate dehydrogenase kinase regulates hepatitis C virus replication |
title_full | Pyruvate dehydrogenase kinase regulates hepatitis C virus replication |
title_fullStr | Pyruvate dehydrogenase kinase regulates hepatitis C virus replication |
title_full_unstemmed | Pyruvate dehydrogenase kinase regulates hepatitis C virus replication |
title_short | Pyruvate dehydrogenase kinase regulates hepatitis C virus replication |
title_sort | pyruvate dehydrogenase kinase regulates hepatitis c virus replication |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4965757/ https://www.ncbi.nlm.nih.gov/pubmed/27471054 http://dx.doi.org/10.1038/srep30846 |
work_keys_str_mv | AT junggwonsoo pyruvatedehydrogenasekinaseregulateshepatitiscvirusreplication AT jeonjaehan pyruvatedehydrogenasekinaseregulateshepatitiscvirusreplication AT choiyeonkyung pyruvatedehydrogenasekinaseregulateshepatitiscvirusreplication AT jangseyoung pyruvatedehydrogenasekinaseregulateshepatitiscvirusreplication AT parksooyoung pyruvatedehydrogenasekinaseregulateshepatitiscvirusreplication AT kimsungwoo pyruvatedehydrogenasekinaseregulateshepatitiscvirusreplication AT byunjunkyu pyruvatedehydrogenasekinaseregulateshepatitiscvirusreplication AT kimmikyung pyruvatedehydrogenasekinaseregulateshepatitiscvirusreplication AT leesungwoo pyruvatedehydrogenasekinaseregulateshepatitiscvirusreplication AT shineuicheol pyruvatedehydrogenasekinaseregulateshepatitiscvirusreplication AT leeinkyu pyruvatedehydrogenasekinaseregulateshepatitiscvirusreplication AT kangyuna pyruvatedehydrogenasekinaseregulateshepatitiscvirusreplication AT parkkeungyu pyruvatedehydrogenasekinaseregulateshepatitiscvirusreplication |