Inhibition of pyruvate dehydrogenase kinase 2 protects against hepatic steatosis through modulation of tricarboxylic acid cycle anaplerosis and ketogenesis

Younghoon Go, Ji Yun Jeong, Nam Ho Jeoung, Jae Han Jeon, Bo Yoon Park, Hyeon Ji Kang, Chae Myeong Ha, Young Keun Choi, Sun Joo Lee, Hye Jin Ham, Byung Gyu Kim, Keun Gyu Park, So Young Park, Chul Ho Lee, Cheol Soo Choi, Tae Sik Park, W. N. Paul Lee, Robert Harris, In Kyu Lee

Research output: Contribution to journalArticle

17 Scopus citations

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. Wildtype 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.

Original languageEnglish (US)
Pages (from-to)2876-2887
Number of pages12
JournalDiabetes
Volume65
Issue number10
DOIs
StatePublished - Oct 1 2016

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Go, Y., Jeong, J. Y., Jeoung, N. H., Jeon, J. H., Park, B. Y., Kang, H. J., Ha, C. M., Choi, Y. K., Lee, S. J., Ham, H. J., Kim, B. G., Park, K. G., Park, S. Y., Lee, C. H., Choi, C. S., Park, T. S., Paul Lee, W. N., Harris, R., & Lee, I. K. (2016). Inhibition of pyruvate dehydrogenase kinase 2 protects against hepatic steatosis through modulation of tricarboxylic acid cycle anaplerosis and ketogenesis. Diabetes, 65(10), 2876-2887. https://doi.org/10.2337/db16-0223