Etomoxir‐induced increase in UCP3 supports a role of uncoupling protein 3 as a mitochondrial fatty acid anion exporter

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Abstract
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 ~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.
Funding Information
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek
  • International Life Sciences Institute Research Foundation