Pyruvate dehydrogenase kinase 4 expression is synergistically induced by AMP-activated protein kinase and fatty acids.
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.
Houten
S M
SM
Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. s.m.houten@amc.uva.nl
Chegary
M
M
Te Brinke
H
H
Wijnen
W J
WJ
Glatz
J F C
JF
Luiken
J J F P
JJ
Wijburg
F A
FA
Wanders
R J A
RJ
D055372:AMP-Activated Protein Kinases / Q000502:physiology*; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000818:Animals; D015687:Cell Hypoxia; D002478:Cells, Cultured; D004734:Energy Metabolism / Q000502:physiology; D004789:Enzyme Activation; D005227:Fatty Acids / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic; D005947:Glucose / Q000378:metabolism; D008024:Ligands; D032383:Myocytes, Cardiac / Q000378:metabolism; D010084:Oxidation-Reduction; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists; D011494:Protein Kinases / Q000096:biosynthesis*; D051381:Rats
D005227:Fatty Acids; D008024:Ligands; D047492:Peroxisome Proliferator-Activated Receptors; D011494:Protein Kinases; C403287:pyruvate dehydrogenase kinase 4; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase; D005947:Glucose