Abstract.
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.
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S. M. Houten, M. Chegary: These two authors contributed equally to this work.
Received 11 July 2008; received after revision 26 January 2009; accepted 02 February 2009
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Houten, S.M., Chegary, M., te Brinke, H. et al. Pyruvate dehydrogenase kinase 4 expression is synergistically induced by AMP-activated protein kinase and fatty acids. Cell. Mol. Life Sci. 66, 1283–1294 (2009). https://doi.org/10.1007/s00018-009-9066-x
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DOI: https://doi.org/10.1007/s00018-009-9066-x