Pyruvate dehydrogenase kinase 4 expression is synergistically induced by AMP-activated protein kinase and fatty acids

• Published in: Cellular and molecular life sciences : CMLS Vol. 66; no. 7; pp. 1283 - 1294
• Main Authors: Houten, S. M, Chegary, M, te Brinke, H, Wijnen, W. J, Glatz, J. F. C, Luiken, J. J. F. P, Wijburg, F. A, Wanders, R. J. A
• Format: Journal Article
• Language: English
• Published: Basel Basel : Birkhäuser-Verlag 01-04-2009; Birkhäuser-Verlag; Springer Nature B.V
• Subjects: Acetyl-CoA Carboxylase - metabolism; AMP-activated protein kinase; AMP-Activated Protein Kinases - physiology; Animals; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cell Biology; Cell Hypoxia; Cells, Cultured; Dehydrogenase; Energy; Energy Metabolism - physiology; Energy sources; Enzyme Activation; Fatty acids; Fatty Acids - physiology; Gene Expression Regulation, Enzymologic; Glucose; Glucose - metabolism; Hypoxia; Kinases; Life Sciences; Ligands; Metabolism; Myocytes, Cardiac - metabolism; Oxidation; Oxidation-Reduction; Peroxisome Proliferator-Activated Receptors - agonists; Protein Kinases - biosynthesis; pyruvate dehydrogenase; pyruvate dehydrogenase kinase 4; Rats; Research Article; Studies; pyruvate dehydrogenase; Glucose metabolism; hypoxia; pyruvate dehydrogenase kinase 4; fatty acids; AMP-activated protein kinase
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-009-9066-x

Organs are flexible as to which substrates they will use to maintain energy homeostasis. Under well-fed conditions, glucose is a preferred substrate for oxidation. During fasting, fatty acid oxidation will become a more important energy source. Glucose oxidation is decreased by fatty acids, a process in which the pyruvate dehydrogenase complex (PDH) and its regulator pyruvate dehydrogenase kinase 4 (PDK4) play important roles. It is currently unknown how energy status influences PDH activity. We show that AMP-activated protein kinase (AMPK) activation by hypoxia and AICAR treatment combined with fatty acid administration synergistically induce PDK4 expression. We provide evidence that AMPK activation modulates ligand-dependent activation of peroxisome proliferator-activated receptor. Finally, we show that this synergistic induction of PDK4 decreases cellular glucose oxidation. In conclusion, AMPK and fatty acids play a direct role in fuel selection in response to cellular energy status in order to spare glucose.