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...

Full description

Saved in:
Bibliographic Details
Published in:Scientific reports 2016-07, Vol.6 (1), p.30846-30846, Article 30846
Main Authors: 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
Format: Article
Language:English
Subjects:
Adult
Aged
Antiviral Agents - pharmacology
Azepines - pharmacology
Cell Line
Dichloroacetic Acid - pharmacology
Glucokinase - metabolism
Glycolysis
Hepacivirus - physiology
Hepatocytes - cytology
Hepatocytes - metabolism
Hepatocytes - virology
Humans
Hypoxia-Inducible Factor 1, alpha Subunit - metabolism
Interferon-alpha - pharmacology
Liver - metabolism
Liver - pathology
Liver - virology
Middle Aged
Protein-Serine-Threonine Kinases - antagonists & inhibitors
Protein-Serine-Threonine Kinases - genetics
Protein-Serine-Threonine Kinases - metabolism
Proto-Oncogene Proteins c-myc - antagonists & inhibitors
Proto-Oncogene Proteins c-myc - genetics
Proto-Oncogene Proteins c-myc - metabolism
Ribavirin - pharmacology
RNA Interference
Triazoles - pharmacology
Virus Replication - drug effects
Virus Replication - physiology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:2045-2322
2045-2322
DOI:10.1038/srep30846