Etomoxir-induced increase in UCP3 supports a role of uncoupling protein 3 as a mitochondrial fatty acid anion exporter.
The physiological function of human uncoupling protein-3 is still unknown. Uncoupling protein-3 is increased during fasting and high-fat feeding. In these situations the availability of fatty acids to the mitochondria exceeds the capacity to metabolize fatty acids, suggesting a role for uncoupling protein-3 in handling of non-metabolizable fatty acids. To test the hypothesis that uncoupling protein-3 acts as a mitochondrial exporter of non-metabolizable fatty acids from the mitochondrial matrix, we gave human subjects Etomoxir (which blocks mitochondrial entry of fatty acids) or placebo in a cross-over design during a 36-h stay in a respiration chamber. Etomoxir inhibited 24-h fat oxidation and fat oxidation during exercise by approximately 14-19%. Surprisingly, uncoupling protein-3 content in human vastus lateralis muscle was markedly up-regulated within 36 h of Etomoxir administration. Up-regulation of uncoupling protein-3 was accompanied by lowered fasting blood glucose and increased translocation of glucose transporter-4. These data support the hypothesis that the physiological function of uncoupling protein-3 is to facilitate the outward transport of non-metabolizable fatty acids from the mitochondrial matrix and thus prevents mitochondria from the potential deleterious effects of high fatty acid levels. In addition our data show that up-regulation of uncoupling protein-3 can be beneficial in the treatment of type 2 diabetes.
Nutrition and Toxicology Research Institute Maastricht, Department of Human Biology, Maastricht University, 6200 MD Maastricht, The Netherlands. p.schrauwen@hb.unimaas.nl
Patrick
P
Schrauwen
Vera
V
Hinderling
Matthijs K C
MK
Hesselink
Gert
G
Schaart
Esther
E
Kornips
Wim H M
WH
Saris
Margriet
M
Westerterp-Plantenga
Wolfgang
W
Langhans
D000328:Adult; D001692:Biological Transport / Q000187:drug effects; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors; D002352:Carrier Proteins / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002940:Circadian Rhythm / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004852:Epoxy Compounds / Q000494:pharmacology*; D015444:Exercise / Q000502:physiology; D005080:Exercise Test; D005227:Fatty Acids / Q000097:blood / Q000378:metabolism*; D051275:Glucose Transporter Type 4; D006801:Humans; D007473:Ion Channels; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D024101:Mitochondrial Proteins; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D000071247:Uncoupling Protein 3
D001786:Blood Glucose; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D005227:Fatty Acids; D051275:Glucose Transporter Type 4; D007473:Ion Channels; D024101:Mitochondrial Proteins; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; C495692:SLC2A4 protein, human; C000604392:UCP3 protein, human; D000071247:Uncoupling Protein 3; D002334:Carnitine O-Palmitoyltransferase; C054207:etomoxir