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Diabetes. 2016 Oct;65(10):2876-87. doi: 10.2337/db16-0223. Epub 2016 Jul 6.

Inhibition of Pyruvate Dehydrogenase Kinase 2 Protects Against Hepatic Steatosis Through Modulation of Tricarboxylic Acid Cycle Anaplerosis and Ketogenesis.

Author information

1
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.
2
Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, South Korea.
3
Department of Pharmaceutical Science and Technology, Catholic University of Daegu, Gyeongsan, South Korea.
4
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.
5
Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University, Daegu, South Korea.
6
Department of Physiology, College of Medicine, Yeungnam University, Daegu, South Korea.
7
Disease Model Research Center, Korea Research Institute of Bioscience & Biotechnology, Daejeon, South Korea.
8
Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Inchon, South Korea.
9
Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA.
10
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.
11
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.

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.

PMID:
27385159
DOI:
10.2337/db16-0223
[Indexed for MEDLINE]
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