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then be able to extract more esterified fatty acids from the cytoplasm, and the level of nonesterified fatty acids entering the mitochondria will drop. Patients suffering from ribofla- vin responsive multiple acylCoA dehydrogenase deficiency, a rare mitochondrial myopathy, are characterized by se- verely hampered fat oxidation and excessive muscular stor- age of lipids, which can be reversed partly by treatment with riboflavin. Untreated riboflavin responsive multiple acyl- CoA dehydrogenase deficiency patients show decreased oxidative capacity, excessive intramyocellular storage of lipids, and significant increases in UCP3 mRNA and protein (94). Treatment with riboflavin induced a return of fat oxidative capacity to control values and induced a signifi- cant drop in intramyocellular lipids. These notable changes in fat oxidation were accompanied by a return of UCP3 protein levels to control values (94). This indicates that restoration of fat oxidative capacity with simultaneous de- cline in fatty acid supply is followed by a rapid decline in UCP3 protein. Once more, this study supports the hypoth- esis that UCP3 exports fatty acid anions from the mitochon- drial matrix. showed that UCP3 protein increases if the supply of fatty acids to the mitochondria exceeds fat oxidative capacity. Also, data are available indicating that the increased UCP3 levels can be normalized if fat oxidative capacity is en- hanced. Although evidence that UCP3 is involved in fatty acid metabolism is compelling, none of the studies pre- sented provide direct and definitive proof that UCP3 indeed facilitates outward translocation of fatty acids from the mitochondrial matrix as hypothesized before (71,86). Based on knowledge derived from studies of UCP1, pio- neering studies all focused on a putative role for UCP3 in energy expenditure. Cell and transgenic animal studies sug- gest that overexpression of UCP3 results in increased en- ergy expenditure. It should be noted, however, that these results do not necessarily reflect human physiology, be- cause it was shown in the cell and transgenic studies that the uncoupling observed was noninducible, as was anticipated given the observations in UCP1-expressing systems. De- spite reports showing associations between the UCP3 gene and markers for energy expenditure under a wide range of conditions, there are no compelling data unequivocally link- ing UCP3 to energy expenditure. The observation that fatty acid levels significantly affect UCP3 expression has given UCP3 a probable role in fatty acid handling and/or oxida- tion. Emerging data indicate that the primary physiological from the mitochondrial matrix in exchange for a proton. The fatty acid anions exported may either originate from hydro- lysis of fatty acid esters by an MTE1, or they may have entered the mitochondria as nonesterified fatty acids by incorporating into and flip-flopping across the mitochon- drial innermembrane. If UCP3 indeed functions to export fatty acid anions from the mitochondrial matrix, it may have an important role in protecting mitochondria against the detrimental effects of high fatty acid levels. By doing so, UCP3 may help to maintain mitochondrial oxidative capac- ity and may be of importance in the prevention and/or treatment of obesity and diabetes. Clearly, future studies are needed to test these concepts and reconsider the role of UCP3 in obesity. was prepared for submission. The research of P.S. has been made possible by fellowships of the Royal Netherlands Academy of Arts and Sciences and the Netherlands Orga- nization for Scientific Research. The authors thank Dr. P. Frederik for preparation of the immnoelectron microscopy samples. mitochondria responsible for regulating energy dissipation. Experientia Suppl. 1978;32:89 93. rate. Am J Physiol. 1996;271(4 Pt 1):C1380 9. respiration rate in working skeletal muscle and liver and to SMR. Am J Physiol. 1999;276(3 Pt 1):C6929. Nat Genet. 1997;15:269 72. with tissue-specific expression. FEBS Lett. 1997;408:39 42. haps the only one? New perspectives on UCP1, UCP2, and UCP3 in the light of the bioenergetics of the UCP1-ablated mice. J Bioenerg Biomembr. 1999;31:47591. hormone, beta3-adrenergic agonists, and leptin. J Biol Chem. 1997;272:24129 32. |
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