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observed in systems expressing UCP3 abundantly (86). This futile cycle may serve to liberate coenzyme A and regener- ate the supply of coenzyme A-SH required for other meta- bolic processes within the mitochondria. ing in cytosol) across the inner mitochondrial membrane or by generation of nonesterified fatty acid by hydrolysis of fatty acylCoA by a mitochondrial thioesterase], both hy- potheses propose that the primary role of UCP3 is the outward translocation of fatty acids away from the mito- chondrial matrix. It should be noted that we hypothesize that fatty acid anion export is essential to prevent mitochondrial damage (e.g., by lipid peroxidation or damage to mitochon- drial DNA), whereas Himms-Hagen and Harper propose that fatty acid anion export serves to liberate CoASH re- quired for other metabolic processes. Himms-Hagen and Harper as support for their hypothesis that UCP3 is an outward translocator of fatty acids gener- ated by MTE1. As the levels of UCP3 expression in the UCP3-tg mice greatly exceed physiological levels, the au- thors extended their findings in obese and insulin-resistant (db/db) mice and in their lean nondiabetic controls with endogenous UCP3 expression. In these mice, selective agonists of peroxisome proliferator-activated receptors (PPAR) and ingly, under basal conditions, db/db mice had increased skeletal muscle levels of UCP3 and MTE1 compared with their controls (88). If treated with rosiglitazone or the Wy- compound, UCP3 and MTE1 were concordantly decreased compared with nondiabetic controls. The authors concluded that if changes in UCP3 mRNA occurred, these were com- plementary with changes in MTE1, suggesting that they are involved in the same metabolic pathway, either in response to, or as regulators of, fatty acid oxidation (88). ditions described. It should be noted, however, that in both experiments in which endogenous UCP3 was induced (88,89), this was achieved by treatment with agonists of either PPAR observed concerted up-regulation of UCP3 and MTE1 may reflect their PPAR responsiveness rather than a functional coupling between the two genes. as a fatty acid anion exporter. Detailed examination to elucidate if the transactivation of MTE1 and UCP3 also occurs in humans and after nonpharmaceutical induction of the UCP3 gene is required. Oxidation in Relation to UCP3 Expression to test the feasibility that UCP3 could act as a fatty acid anion exporter, we blocked mitochondrial entry of fatty acids through CAT1 by administering Etomoxir (HPO Wolf, Projekt Entwicklung GmbH, Allensbach, Germany) for 36 hours to human subjects while they were consuming high-fat diets (to increase fatty acid supply). As a conse- quence, the concentration of sarcoplasmic FFAs will rise, and the fraction of fatty acids entering the mitochondria in their nonesterified form increases. Using respiration cham- bers, we showed that Etomoxir effectively interfered with fat oxidation, given the decreased fat and increased carbo- hydrate oxidation (93). In all subjects, UCP3 levels were increased after Etomoxir treatment compared with controls, resulting in an average increase of 67% at the UCP3 protein level after 36 hours! Furthermore, we observed a negative correlation between the decrease in fat oxidation after Eto- moxir treatment and the increase in UCP3 protein (93). These data are highly compatible with our hypothesis that UCP3 exports fatty acid anions derived from "flip-flop" driven entry of nonesterified fatty acids. In addition, it should be noted that blockade of CAT1 is an experimental condition in which the entry of fatty acylCoA into the mitochondria is reduced, making it unlikely that the induc- tion of UCP3 was related to the action of MTE1. tive capacity. In rats rendered diabetic by treatment of streptozotocin, decreased fatty acid oxidative capacity was associated with increased UCP3 mRNA levels in the heart (81). Under healthy conditions, the heart relies almost ex- clusively on fat oxidation and is well equipped to efficiently handle lipids over a wide range of conditions. When think- ing of UCP3 as a mitochondrial fatty acid anion exporter, it is not striking that UCP3 has been reported only at very modest protein levels in cardiac muscle. We recently con- firmed the results of Hidaka et al. (81), showing a signifi- cant and massive increase in UCP3 mRNA and protein expression, which was closely associated with increased cytosolic fatty acids in the hearts of streptozotocin-treated rats (van der Vusse et al., unpublished data). This observa- tion directly links the change in UCP3 to the change in sarcoplasmic nonesterified fatty acids. |
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