1. Inhibition of Pyruvate Dehydrogenase Kinase 2 Protects Against Hepatic Steatosis Through Modulation of Tricarboxylic Acid Cycle Anaplerosis and Ketogenesis
- Author
-
Hyung-Tae Kang, Keung-Shik Park, Chae-Myeong Ha, Ihn-Chong Lee, Ji Yun Jeong, H J Ham, Youngdal Choi, So-Young Park, Sun Joo Lee, Nam Ho Jeoung, Jae-Han Jeon, Robert A. Harris, Cheol Soo Choi, Younghoon Go, Tae-Sik Park, W P Lee, Bo-Yoon Park, Byeongyeon Kim, and Chul-Ho Lee
- Subjects
0301 basic medicine ,Male ,Oxaloacetic Acid ,medicine.medical_specialty ,Pyruvate dehydrogenase kinase ,Endocrinology, Diabetes and Metabolism ,Citric Acid Cycle ,030209 endocrinology & metabolism ,Pyruvate Dehydrogenase Complex ,Protein Serine-Threonine Kinases ,Diet, High-Fat ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Insulin resistance ,Internal medicine ,Nonalcoholic fatty liver disease ,Ketogenesis ,Pyruvic Acid ,Internal Medicine ,medicine ,Animals ,Mice, Knockout ,Chemistry ,Lipogenesis ,Pyruvate Dehydrogenase Acetyl-Transferring Kinase ,Pyruvate dehydrogenase complex ,medicine.disease ,Citric acid cycle ,Fatty Liver ,Malonyl Coenzyme A ,030104 developmental biology ,Endocrinology ,Glucose ,Liver ,Steatosis ,Insulin Resistance - 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.
- Published
- 2016