title: Pyruvate dehydrogenase kinase regulates hepatitis C virus replication.
abstract: 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.
authors.affiliation: Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Republic of Korea.|Leading-edge Research Center for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, Republic of Korea.
authors.forename: Gwon-Soo
authors.initials: GS
authors.lastname: Jung
authors.affiliation: Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Republic of Korea.|Leading-edge Research Center for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, Republic of Korea.
authors.forename: Jae-Han
authors.initials: JH
authors.lastname: Jeon
authors.affiliation: Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Republic of Korea.|Leading-edge Research Center for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, Republic of Korea.
authors.forename: Yeon-Kyung
authors.initials: YK
authors.lastname: Choi
authors.affiliation: Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
authors.forename: Se Young
authors.initials: SY
authors.lastname: Jang
authors.affiliation: Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Park
authors.affiliation: Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Republic of Korea.|Leading-edge Research Center for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, Republic of Korea.
authors.forename: Sung-Woo
authors.initials: SW
authors.lastname: Kim
authors.affiliation: Leading-edge Research Center for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, Republic of Korea.
authors.forename: Jun-Kyu
authors.initials: JK
authors.lastname: Byun
authors.affiliation: Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Republic of Korea.
authors.forename: Mi-Kyung
authors.initials: MK
authors.lastname: Kim
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Republic of Korea.
authors.forename: Sungwoo
authors.initials: S
authors.lastname: Lee
authors.affiliation: Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea.
authors.forename: Eui-Cheol
authors.initials: EC
authors.lastname: Shin
authors.affiliation: Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Republic of Korea.|Leading-edge Research Center for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, Republic of Korea.
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Lee
authors.affiliation: Department of Pathology, Keimyung University School of Medicine, Daegu, Republic of Korea.
authors.forename: Yu Na
authors.initials: YN
authors.lastname: Kang
authors.affiliation: Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Republic of Korea.|Leading-edge Research Center for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, Republic of Korea.
authors.forename: Keun-Gyu
authors.initials: KG
authors.lastname: Park
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000494:pharmacology; D001381:Azepines / Q000494:pharmacology; D002460:Cell Line; D003999:Dichloroacetic Acid / Q000494:pharmacology; D005941:Glucokinase / Q000378:metabolism; D006019:Glycolysis; D016174:Hepacivirus / Q000502:physiology*; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism / Q000821:virology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D016898:Interferon-alpha / Q000494:pharmacology; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D034622:RNA Interference; D012254:Ribavirin / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology*
chemical_list: C561695:(+)-JQ1 compound; D000998:Antiviral Agents; D001381:Azepines; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016898:Interferon-alpha; C000631429:PDK1 protein, human; C000631431:PDK3 protein, human; D016271:Proto-Oncogene Proteins c-myc; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D014230:Triazoles; D012254:Ribavirin; D003999:Dichloroacetic Acid; D005941:Glucokinase; D017346:Protein Serine-Threonine Kinases