Uncoupling protein 3 as a mitochondrial fatty acid anion exporter

Abstract

In contrast to UCP1, the primary function of UCP3 is not the dissipation of energy. Rather, several lines of evidence suggest that UCP3 is related to cellular long-chain fatty acid homeostasis. If long-chain fatty acids enter the mitochondrial matrix in their non-esterified form, they cannot be metabolized and may exert deleterious effects. To test the feasibility that UCP3 exports fatty acid anions, we systematically interfered at distinct steps in the fatty acid metabolism pathway, thereby creating conditions in which the entry of (non-esterified) fatty acids into the mitochondrial matrix is enhanced. First, reducing the cellular fatty acid binding capacity, known to increase cytosolic concentrations of non-esterified fatty acids, up-regulated UCP3 5.3-fold. Second, inhibition of mitochondrial entry of esterified long-chain fatty acids upregulated UCP3 by 1.9-fold. Third, high-fat diets, to increase mitochondrial supply of nonesterified long-chain fatty acids exceeding oxidative capacity, up-regulated UCP3 twofold. However, feeding a similar amount of medium-chain fatty acids, which can be oxidized inside the mitochondrial matrix and therefore do not need to be exported from the matrix, did not affect UCP3 protein levels. These data are compatible with a physiological function of UCP3 in facilitating outward transport of long-chain fatty acid anions, which cannot be oxidized, from the mitochondrial matrix.Key words: UCP3 • fatty acid transport • mitochondria • high-fat diet n contrast to the brown adipose tissue-specific UCP1, there is ample evidence that the physiological function of UCP3 is not in energy dissipation. For example, fasting, an energy preserving condition, rapidly up-regulates UCP3 (1). We have recently demonstrated in humans that a diet-induced up-regulation of UCP3 did not affect mitochondrial coupling, suggesting that the primary function of UCP3 is not mitochondrial uncoupling (2). Rather, several lines of evidence suggest that UCP3 is related to cellular fatty acid metabolism. Thus, I aberrations in whole-body fat oxidation were observed in humans with an exon-6 splice donor mutation in UCP3 (3), as well as in UCP3 knockout mice (4). Furthermore, in skeletal muscle UCP3 is rapidly up-regulated during fasting (1), acute exercise (5, 6), and high dietary fat-intake (7,8), all situations in which fat metabolism is affected. In addition, UCP3 protein content declines in situations in which fat oxidative capacity is improved, such as after endurance training (9, 10) and after weight reduction (11,12), and UCP3 has lowest expression in Type 1 muscle fibers, which are characterized by a high fat oxidative capacity (13,14).This pattern of regulation of UCP3 can consistently be explained by considering the balance between fatty acid delivery to mitochondria and their capacity to oxidize fatty acids. In situations characterized by a positive balance (i.e., fatty acid delivery exceeds oxidative capacity), such as fasting, high-fat intake, acute exercise, and in Type 2b fibers, UCP3 levels are...

Upregulation of peroxisome proliferator-activated receptor gamma coactivator gene (PGC1A) during weight loss is related to insulin sensitivity but not to energy expenditure

“…Thus, the role of UCP3 would be to protect muscle tissue against lipotoxicity, rather than to regulate energy expenditure. Schrauwen et al [42] have suggested There was a significant and independent relationship of BMI (p= 0.002) and MFN2 (p=0.006) with insulin sensitivity measured in morbidly obese women before and during RYGB-induced weight loss that UCP3 could contribute to outward translocation of NEFA, occurring when NEFA availability exceeds mitochondrial oxidative capacity. This mechanism would protect the mitochondria from NEFA accumulation.…”

Adaptive thermogenesis and uncoupling proteins: a reappraisal of their roles in fat metabolism and energy balance

“…However, one wonders about the validity of rejecting carrier function solely on the basis of amino-acid identity to the carnitine carrier. A number of biochemical models have in fact been proposed in which these UCP1-homologues would operate as fatty-acid carriers across the mitochondria, and the putative function of UCP2 and/or UCP3 would be to export fatty acids out of the mitochondria when fatty acid supply or oxidation predominates, such as in the skeletal muscle during fasting and high-fat feeding [77][78][79]). Most of the proposed models have focused on UCP3, primarily because of the inability to detect UCP2 protein in organs/tissues known to be important sites of fat metabolism (skeletal muscle, heart, brown adipose tissue).…”

“…In other models, UCP2 and/or UCP3 are postulated to be involved in the translocation of the fatty acid anions from the matrix side to the cytosolic side of the mitochondrial membrane [42,71,79]. The fatty acid anions would be protonated, and the UCP1-homologues would then dflipflopT these neutral fatty acids back to the matrix side [70,71,79], resulting in a lowering of the proton gradient and hence increased heat production.…”

“…The fatty acid anions would be protonated, and the UCP1-homologues would then dflipflopT these neutral fatty acids back to the matrix side [70,71,79], resulting in a lowering of the proton gradient and hence increased heat production. Within these models of fatty acid cycling, therefore, the UCP1-homologues Table 4 A link between skeletal muscle UCP2/UCP3 gene expression and regulation of lipids as fuel substrate in response to fasting would exert an uncoupling effect by being involved in translocating an excessive amount of fatty acid anions out of the mitochondrion.…”

Capsiate administration results in an uncoupling protein-3 downregulation, an enhanced muscle oxidative capacity and a decreased abdominal fat content in vivo

“…3 It has been also proposed that UCP3 could behave as a mitochondrial fatty acid anion transporter thereby mitigating lipotoxicity. 4 Overall, the metabolic modifications associated with UCP3 expression and more particularly muscle energy consumption and fat metabolism warrant further investigations.…”