title: Inhibition of Pyruvate Dehydrogenase Kinase 2 Protects Against Hepatic Steatosis Through Modulation of Tricarboxylic Acid Cycle Anaplerosis and Ketogenesis.
abstract: Hepatic steatosis is associated with increased insulin resistance and tricarboxylic acid (TCA) cycle flux, but decreased ketogenesis and pyruvate dehydrogenase complex (PDC) flux. This study examined whether hepatic PDC activation by inhibition of pyruvate dehydrogenase kinase 2 (PDK2) ameliorates these metabolic abnormalities. Wild-type mice fed a high-fat diet exhibited hepatic steatosis, insulin resistance, and increased levels of pyruvate, TCA cycle intermediates, and malonyl-CoA but reduced ketogenesis and PDC activity due to PDK2 induction. Hepatic PDC activation by PDK2 inhibition attenuated hepatic steatosis, improved hepatic insulin sensitivity, reduced hepatic glucose production, increased capacity for β-oxidation and ketogenesis, and decreased the capacity for lipogenesis. These results were attributed to altered enzymatic capacities and a reduction in TCA anaplerosis that limited the availability of oxaloacetate for the TCA cycle, which promoted ketogenesis. The current study reports that increasing hepatic PDC activity by inhibition of PDK2 ameliorates hepatic steatosis and insulin sensitivity by regulating TCA cycle anaplerosis and ketogenesis. The findings suggest PDK2 is a potential therapeutic target for nonalcoholic fatty liver disease.
authors.affiliation: Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, South Korea Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University, Daegu, South Korea.
authors.forename: Younghoon
authors.initials: Y
authors.lastname: Go
authors.affiliation: Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, South Korea.
authors.forename: Ji Yun
authors.initials: JY
authors.lastname: Jeong
authors.affiliation: Department of Pharmaceutical Science and Technology, Catholic University of Daegu, Gyeongsan, South Korea.
authors.forename: Nam Ho
authors.initials: NH
authors.lastname: Jeoung
authors.affiliation: Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, South Korea Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University, Daegu, South Korea.
authors.forename: Jae-Han
authors.initials: JH
authors.lastname: Jeon
authors.affiliation: Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, South Korea BK21 Plus KNU Biomedical Convergence Programs at Kyungpook National University, Daegu, South Korea.
authors.forename: Bo-Yoon
authors.initials: BY
authors.lastname: Park
authors.affiliation: Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, South Korea BK21 Plus KNU Biomedical Convergence Programs at Kyungpook National University, Daegu, South Korea.
authors.forename: Hyeon-Ji
authors.initials: HJ
authors.lastname: Kang
authors.affiliation: Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, South Korea BK21 Plus KNU Biomedical Convergence Programs at Kyungpook National University, Daegu, South Korea.
authors.forename: Chae-Myeong
authors.initials: CM
authors.lastname: Ha
authors.affiliation: Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, South Korea.
authors.forename: Young-Keun
authors.initials: YK
authors.lastname: Choi
authors.affiliation: Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, South Korea.
authors.forename: Sun Joo
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University, Daegu, South Korea.
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Ham
authors.affiliation: Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University, Daegu, South Korea.
authors.forename: Byung-Gyu
authors.initials: BG
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, South Korea Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University, Daegu, South Korea.
authors.forename: Keun-Gyu
authors.initials: KG
authors.lastname: Park
authors.affiliation: Department of Physiology, College of Medicine, Yeungnam University, Daegu, South Korea.
authors.forename: So Young
authors.initials: SY
authors.lastname: Park
authors.affiliation: Disease Model Research Center, Korea Research Institute of Bioscience & Biotechnology, Daejeon, South Korea.
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Inchon, South Korea.
authors.forename: Cheol Soo
authors.initials: CS
authors.lastname: Choi
authors.affiliation: Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Inchon, South Korea.
authors.forename: Tae-Sik
authors.initials: TS
authors.lastname: Park
authors.affiliation: Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA.
authors.forename: W N Paul
authors.initials: WN
authors.lastname: Lee
authors.affiliation: Richard L. Roudebush VA Medical Center, Indianapolis, IN Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN raharris@iu.edu leei@knu.ac.kr.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harris
authors.affiliation: Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, South Korea Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University, Daegu, South Korea BK21 Plus KNU Biomedical Convergence Programs at Kyungpook National University, Daegu, South Korea raharris@iu.edu leei@knu.ac.kr.
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Lee
mesh_terms: D000818:Animals; D002952:Citric Acid Cycle / Q000235:genetics / Q000502:physiology; D059305:Diet, High-Fat / Q000009:adverse effects; D005234:Fatty Liver / Q000201:enzymology* / Q000209:etiology / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D007333:Insulin Resistance; D050155:Lipogenesis / Q000502:physiology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008316:Malonyl Coenzyme A / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D062907:Oxaloacetic Acid / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism
chemical_list: C000631435:Pdk2 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex; D062907:Oxaloacetic Acid; D008316:Malonyl Coenzyme A; D019289:Pyruvic Acid; D017346:Protein Serine-Threonine Kinases; D005947:Glucose