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: 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 A Harris, In-Kyu Lee
• Journal: Diabetes (Diabetes) Vol. 65 Issue 10 Pg. 2876-87 (10 2016) ISSN: 1939-327X [Electronic] United States
• PMID: 27385159 (Publication Type: Journal Article)
• Copyright: © 2016 by the American Diabetes Association.

Chemical References

• Pdk2 protein, mouse
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase
• Pyruvate Dehydrogenase Complex
• Oxaloacetic Acid
• Malonyl Coenzyme A
• Pyruvic Acid
• Protein Serine-Threonine Kinases
• Glucose

Topics

• Animals
• Citric Acid Cycle (genetics, physiology)
• Diet, High-Fat (adverse effects)
• Fatty Liver (enzymology, etiology, metabolism)
• Glucose (metabolism)
• Insulin Resistance
• Lipogenesis (physiology)
• Liver (metabolism, pathology)
• Male
• Malonyl Coenzyme A (metabolism)
• Mice
• Mice, Knockout
• Oxaloacetic Acid (metabolism)
• Protein Serine-Threonine Kinases (deficiency, genetics, metabolism)
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase
• Pyruvate Dehydrogenase Complex (metabolism)
• Pyruvic Acid (metabolism)