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Title:   Author  item
                                            Piccolo, Brianitem
                                            GRAPOV, DMITRY - University Of Californiaitem
                                            Adams, Seanitem
                                            HOPPEL, CHARLES - Case Western Reserve University (CWRU)item
                                            GARVEY, W. TIMOTHY - University Of Alabamaitem
                                            FIEHN, OLIVER - University Of Californiaitem
                                            HARPER, MARY-ELLEN - University Of Ottawaitem
                                            Newman, John
  Submitted to: Journal of Federation of American Societies for Experimental Biology
                                    Publication Type: Peer Reviewed Journal
                                    Publication Acceptance Date: 10/31/2010
                                    Publication  Date: 12/10/2010
                                    Citation: Piccolo, B.D., Grapov, D., Adams, S.H., Hoppel, C., Garvey, W., Fiehn, O., Harper, M., Newman, J.W. 2010. Impact of a UCP3 Loss-of-Function Polymorphism on the Plasma Metabolomic Profile in Obese African-American Women. Journal of Federation of American Societies for Experimental Biology. https://doi.org/10.1371/journal.pone.0015234.s002.Interpretive Summary: Interpretive Summary
While skeletal muscle uncoupling protein 3 (UCP3) is thought to facilitate fatty acid oxidation and decrease the production of mitochondrial reactive oxygen species (ROS), this has yet to be demonstrated in humans.  In this study, we investigated the impact of UCP3 on fatty acid metabolism and ROS production by measuring plasma metabolite profiles from people with and without functional UCP3 proteins.  As single nucleotide polyporphism which changes the 304th amino acid in the UCP3 protein from a glycine to an alanine (i.e. G304A UCP3) disrupts UCP3 function and has been associated with reduced whole body fat oxidation.  Therefore, a group of obese African-American women stratified by type 2 diabetes status and UCP3 genotype were studied.  We collected 490 unique measurements using untargeted metabolomics, mediator lipidomics, acylcarnitine profiling and classical clinical chemistry.  Surprisingly, plasma non-esterified fatty acids were not associated with UCP3 genotype.  Rather, the loss of UCP3 function altered amino acid profiles and compounds suggestive of enhanced glycolytic oxidation, likely through pyruvate catabolism, and showed evidence of an increase in the malate-aspartate shuttle, a pathway that allows the continued generation of cellular energy when many systems are inhibited by elevated ROS levels. The UCP3 G/A genotype also decreased plasma antioxidants and amino acids involved in the synthesis of the antioxidant regulator glutathione.    Stearoylethanolamide, a putative modulator of mitochondrial oxidative phosphorylation and biogenesis was also significantly elevated in UCP3 G/A individuals with type 2 diabetes.  Together, our results suggest that the loss of UCP3 function increases mitochondrial-dependent oxidative stress, resulting in a shift of mitochondrial fuel selection from fatty acids toward pyruvate.  Moreover this data suggests that under the enhanced oxidative stress associated with T2D, stearoylethanolamide may be involved in the nitric oxide-dependent compensation to regulate mitochondrial function resulting from the UCP3 dysfunction.
                                Technical Abstract: Technical Abstract
Skeletal muscle uncoupling protein 3 (UCP3) is thought to facilitate fatty acid oxidation and decrease the production of mitochondrial reactive oxygen species (ROS), however this has yet to be proven in humans.  We hypothesized that a plasma metabolomic analysis of a human UCP3 loss-of-function polymorphism would identify metabolites associated with decreased skeletal fatty acid oxidation and oxidative stress derived from increased ROS production.  A cohort of obese African-American women with or without the G304A UCP3 genotype, stratified by type 2 diabetes status, was investigated.  The G304A UCP3 missense polymorphism has been associated with reduced whole body fat oxidation.  We measured 490 metabolites using untargeted metabolomics, mediator lipidomics and acylcarnitine profiling.  Surprisingly, plasma non-esterified fatty acids were not determinants of UCP3 G/A genotype.  Rather, the functional polymorphism altered amino acid profiles and compounds suggestive of enhanced glycolytic oxidation, likely through pyruvate catabolism, and showed evidence of an increase in the malate-aspartate shuttle.  The UCP3 G/A genotype also decreased plasma levels of antioxidants and amino acids involved in glutathione metabolism, potentially indicating enhanced glutathione synthesis.  Stearoylethanolamide, a putative modulator of mitochondrial oxidative phosphorylation and biogenesis was also significantly elevated in T2D UCP3 G/A individuals.  Together, our results suggest that the loss of UCP3 function increases mitochondrial-dependent oxidative stress, resulting in a shift of mitochondrial fuel selection from fatty acids toward pyruvate.  Moreover this data suggest that under the enhanced oxidative stress associated with T2D, stearoylethanolamide may be involved in the nitric oxide-dependent compensation to regulate mitochondrial function resulting from the UCP3 dysfunction.


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