| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Department of Biochemistry, Microbiology & Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada
This hypothesis proposes a physiological role for uncoupling protein-3 (UCP3) in the export of fatty acid anions from muscle and brown adipose tissue (BAT) mitochondria when fatty acids are the predominant substrate being used. It proposes that excess acyl CoA within the mitochondria is hydrolyzed by a mitochondrial acyl CoA thioesterase, yielding fatty acid anion and CoASH. The fatty acid anion is exported to the cytosol by being carried across the inner mitochondrial membrane by UCP3. The CoASH is conserved within the mitochondrion to participate in other reactions for which it is needed during fatty acid oxidation in the ß-oxidation cycle and in the tricarboxylic acid cycle. The export of the fatty acid anion thus permits continued rapid fatty acid oxidation in the face of an oversupply. The hypothesis provides a logical explanation for the observed up-regulation of gene expression for UCP3 in muscle when there is a switch to fatty acid oxidation, as during fasting, and in BAT when fatty acid oxidation is stimulated, as during exposure to cold. It provides a plausible physiological role for UCP3 as a transporter protein, not as an uncoupling protein.
Key Words: uncoupling proteins • fatty acids • skeletal muscle • brown adipose tissue • acyl CoA thioesterase • thermogenesis • cold • mitochondrial carrier proteins
This article has been cited by other articles:
|
|
 |
|
  R. Harmancey, C. R. Wilson, and H. Taegtmeyer Adaptation and Maladaptation of the Heart in Obesity Hypertension, August 1, 2008; 52(2): 181 - 187. [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Mazzatti, M. A. Smith, R. C. Oita, F.-L. Lim, A. J. White, and M. B. Reid Muscle unloading-induced metabolic remodeling is associated with acute alterations in PPAR{delta} and UCP-3 expression Physiol Genomics, July 9, 2008; 34(2): 149 - 161. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. B. Lockridge, M. L. Sailors, D. J. Durgan, O. Egbejimi, W. J. Jeong, M. S. Bray, W. C. Stanley, and M. E. Young Bioinformatic profiling of the transcriptional response of adult rat cardiomyocytes to distinct fatty acidsboxs J. Lipid Res., July 1, 2008; 49(7): 1395 - 1408. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. D. Fink, J. A. Herlein, K. Almind, S. Cinti, C. R. Kahn, and W. I. Sivitz Mitochondrial proton leak in obesity-resistant and obesity-prone mice Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2007; 293(5): R1773 - R1780. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Zungu, M. P. Alcolea, F. J. Garcia-Palmer, M. E. Young, and M. F. Essop Genomic modulation of mitochondrial respiratory genes in the hypertrophied heart reflects adaptive changes in mitochondrial and contractile function Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H2819 - H2825. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. J. Anderson, H. Yamazaki, and P. D. Neufer Induction of Endogenous Uncoupling Protein 3 Suppresses Mitochondrial Oxidant Emission during Fatty Acid-supported Respiration J. Biol. Chem., October 26, 2007; 282(43): 31257 - 31266. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Raichur, P. Lau, B. Staels, and G. E O Muscat Retinoid-related orphan receptor {gamma} regulates several genes that control metabolism in skeletal muscle cells: links to modulation of reactive oxygen species production J. Mol. Endocrinol., July 1, 2007; 39(1): 29 - 44. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. L. King, M. E. Young, J. Kerner, H. Huang, K. M. O'Shea, S. E. H. Alexson, C. L. Hoppel, and W. C. Stanley Diabetes or peroxisome proliferator-activated receptor {alpha} agonist increases mitochondrial thioesterase I activity in heart J. Lipid Res., July 1, 2007; 48(7): 1511 - 1517. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Bezaire, E. L. Seifert, and M.-E. Harper Uncoupling protein-3: clues in an ongoing mitochondrial mystery FASEB J, February 1, 2007; 21(2): 312 - 324. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. de Lange, P. Farina, M. Moreno, M. Ragni, A. Lombardi, E. Silvestri, L. Burrone, A. Lanni, and F. Goglia Sequential changes in the signal transduction responses of skeletal muscle following food deprivation FASEB J, December 1, 2006; 20(14): 2579 - 2581. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. K. Gerber, B. J. Aronow, and M. A. Matlib Activation of a novel long-chain free fatty acid generation and export system in mitochondria of diabetic rat hearts Am J Physiol Cell Physiol, December 1, 2006; 291(6): C1198 - C1207. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Hunt, A. Rautanen, M. A. K. Westin, L. T. Svensson, and S. E. H. Alexson Analysis of the mouse and human acyl-CoA thioesterase (ACOT) gene clusters shows that convergent, functional evolution results in a reduced number of human peroxisomal ACOTs FASEB J, September 1, 2006; 20(11): 1855 - 1864. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Boudina and E. D. Abel Mitochondrial uncoupling: a key contributor to reduced cardiac efficiency in diabetes. Physiology, August 1, 2006; 21: 250 - 258. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Barger, B. M. Barnes, and B. B. Boyer Regulation of UCP1 and UCP3 in arctic ground squirrels and relation with mitochondrial proton leak J Appl Physiol, July 1, 2006; 101(1): 339 - 347. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. R. Costford, S. N. Chaudhry, M. Salkhordeh, and M.-E. Harper Effects of the presence, absence, and overexpression of uncoupling protein-3 on adiposity and fuel metabolism in congenic mice Am J Physiol Endocrinol Metab, June 1, 2006; 290(6): E1304 - E1312. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Durgan, J. K. Smith, M. A. Hotze, O. Egbejimi, K. D. Cuthbert, V. G. Zaha, J. R. B. Dyck, E. D. Abel, and M. E. Young Distinct transcriptional regulation of long-chain acyl-CoA synthetase isoforms and cytosolic thioesterase 1 in the rodent heart by fatty acids and insulin Am J Physiol Heart Circ Physiol, June 1, 2006; 290(6): H2480 - H2497. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. T. Garvey Uncoupling protein 3 and human metabolism. J. Clin. Endocrinol. Metab., April 1, 2006; 91(4): 1226 - 1228. [Full Text] [PDF]
|
|
|
|
|
|
P. Schrauwen, M. Mensink, G. Schaart, E. Moonen-Kornips, J.-P. Sels, E. E. Blaak, A. P. Russell, and M. K. C. Hesselink Reduced Skeletal Muscle Uncoupling Protein-3 Content in Prediabetic Subjects and Type 2 Diabetic Patients: Restoration by Rosiglitazone Treatment J. Clin. Endocrinol. Metab., April 1, 2006; 91(4): 1520 - 1525. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Bevilacqua, J. J. Ramsey, K. Hagopian, R. Weindruch, and M.-E. Harper Long-term caloric restriction increases UCP3 content but decreases proton leak and reactive oxygen species production in rat skeletal muscle mitochondria Am J Physiol Endocrinol Metab, September 1, 2005; 289(3): E429 - E438. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D. MacLellan, M. F. Gerrits, A. Gowing, P. J.S. Smith, M. B. Wheeler, and M.-E. Harper Physiological Increases in Uncoupling Protein 3 Augment Fatty Acid Oxidation and Decrease Reactive Oxygen Species Production Without Uncoupling Respiration in Muscle Cells Diabetes, August 1, 2005; 54(8): 2343 - 2350. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Ravnskjaer, M. Boergesen, B. Rubi, J. K. Larsen, T. Nielsen, J. Fridriksson, P. Maechler, and S. Mandrup Peroxisome Proliferator-Activated Receptor {alpha} (PPAR{alpha}) Potentiates, whereas PPAR{gamma} Attenuates, Glucose-Stimulated Insulin Secretion in Pancreatic {beta}-Cells Endocrinology, August 1, 2005; 146(8): 3266 - 3276. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Jastroch, S. Wuertz, W. Kloas, and M. Klingenspor Uncoupling protein 1 in fish uncovers an ancient evolutionary history of mammalian nonshivering thermogenesis Physiol Genomics, July 14, 2005; 22(2): 150 - 156. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. C. Stanley, F. A. Recchia, and G. D. Lopaschuk Myocardial Substrate Metabolism in the Normal and Failing Heart Physiol Rev, July 1, 2005; 85(3): 1093 - 1129. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Valle, A. Catala-Niell, B. Colom, F. J. Garcia-Palmer, J. Oliver, and P. Roca Sex-related differences in energy balance in response to caloric restriction Am J Physiol Endocrinol Metab, July 1, 2005; 289(1): E15 - E22. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Mostyn, J. C. Litten, K. S. Perkins, P. J. Euden, A. M. Corson, M. E. Symonds, and L. Clarke Influence of size at birth on the endocrine profiles and expression of uncoupling proteins in subcutaneous adipose tissue, lung, and muscle of neonatal pigs Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2005; 288(6): R1536 - R1542. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Tu, J. N. Thupari, E.-K. Kim, M. L. Pinn, T. H. Moran, G. V. Ronnett, and F. P. Kuhajda C75 Alters Central and Peripheral Gene Expression to Reduce Food Intake and Increase Energy Expenditure Endocrinology, January 1, 2005; 146(1): 486 - 493. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. T. Putman, W. T. Dixon, J. A. Pearcey, I. M. MacLean, M. J. Jendral, M. Kiricsi, G. K. Murdoch, and D. Pette Chronic low-frequency stimulation upregulates uncoupling protein-3 in transforming rat fast-twitch skeletal muscle Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2004; 287(6): R1419 - R1426. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Stavinoha, J. W. RaySpellicy, M. F. Essop, C. Graveleau, E. D. Abel, M. L. Hart-Sailors, H. J. Mersmann, M. S. Bray, and M. E. Young Evidence for mitochondrial thioesterase 1 as a peroxisome proliferator-activated receptor-{alpha}-regulated gene in cardiac and skeletal muscle Am J Physiol Endocrinol Metab, November 1, 2004; 287(5): E888 - E895. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A Mostyn, J C Litten, K S Perkins, M C Alves-Guerra, C Pecqueur, B Miroux, M E Symonds, and L Clarke Influence of genotype on the differential ontogeny of uncoupling protein 2 and 3 in subcutaneous adipose tissue and muscle in neonatal pigs J. Endocrinol., October 1, 2004; 183(1): 121 - 131. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Ljubicic, P. J. Adhihetty, and D. A. Hood Role of UCP3 in state 4 respiration during contractile activity-induced mitochondrial biogenesis J Appl Physiol, September 1, 2004; 97(3): 976 - 983. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Chieffi Baccari, R. Monteforte, P. de Lange, F. Raucci, P. Farina, and A. Lanni Thyroid Hormone Affects Secretory Activity and Uncoupling Protein-3 Expression in Rat Harderian Gland Endocrinology, July 1, 2004; 145(7): 3338 - 3345. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Arkinstall, R. J. Tunstall, D. Cameron-Smith, and J. A. Hawley Regulation of metabolic genes in human skeletal muscle by short-term exercise and diet manipulation Am J Physiol Endocrinol Metab, July 1, 2004; 287(1): E25 - E31. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Schrauwen and M. K.C. Hesselink Oxidative Capacity, Lipotoxicity, and Mitochondrial Damage in Type 2 Diabetes Diabetes, June 1, 2004; 53(6): 1412 - 1417. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Bevilacqua, J. J. Ramsey, K. Hagopian, R. Weindruch, and M.-E. Harper Effects of short- and medium-term calorie restriction on muscle mitochondrial proton leak and reactive oxygen species production Am J Physiol Endocrinol Metab, June 1, 2004; 286(5): E852 - E861. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Jastroch, K. Withers, and M. Klingenspor Uncoupling protein 2 and 3 in marsupials: identification, phylogeny, and gene expression in response to cold and fasting in Antechinus flavipes Physiol Genomics, April 13, 2004; 17(2): 130 - 139. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. C. Stanley Myocardial Energy Metabolism During Ischemia and the Mechanisms of Metabolic Therapies Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2004; 9(1_suppl): S31 - S45. [Abstract] [PDF]
|
|
|
|
|
|
C. B. Chan, M. C. Saleh, V. Koshkin, and M. B. Wheeler Uncoupling Protein 2 and Islet Function Diabetes, February 1, 2004; 53(90001): S136 - 142. [Abstract] [Full Text]
|
|
|
|
|
|
S. Le Fur, C. Le Stunff, C. Dos Santos, and P. Bougneres The Common -866 G/A Polymorphism in the Promoter of Uncoupling Protein 2 Is Associated With Increased Carbohydrate and Decreased Lipid Oxidation in Juvenile Obesity Diabetes, January 1, 2004; 53(1): 235 - 239. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. P. Russell, P. Schrauwen, E. Somm, G. Gastaldi, M. K. C. Hesselink, G. Schaart, E. Kornips, S. K. Lo, D. Bufano, J.-P. Giacobino, et al. Decreased Fatty Acid {beta}-Oxidation in Riboflavin-Responsive, Multiple Acylcoenzyme A Dehydrogenase-Deficient Patients Is Associated with an Increase in Uncoupling Protein-3 J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 5921 - 5926. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Masuda, S. Haramizu, K. Oki, K. Ohnuki, T. Watanabe, S. Yazawa, T. Kawada, S.-i. Hashizume, and T. Fushiki Upregulation of uncoupling proteins by oral administration of capsiate, a nonpungent capsaicin analog J Appl Physiol, December 1, 2003; 95(6): 2408 - 2415. [Abstract] [Full Text]
|
|
|
|
|
|
A. M. Rodriguez, P. Roca, M. L. Bonet, C. Pico, P. Oliver, and A. Palou Positive correlation of skeletal muscle UCP3 mRNA levels with overweight in male, but not in female, rats Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2003; 285(4): R880 - R888. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.R. Gosker, P. Schrauwen, M.K.C. Hesselink, G. Schaart, G.J. van der Vusse, E.F.M. Wouters, and A.M.W.J. Schols Uncoupling protein-3 content is decreased in peripheral skeletal muscle of patients with COPD Eur. Respir. J., July 1, 2003; 22(1): 88 - 93. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Koshkin, X. Wang, P. E. Scherer, C. B. Chan, and M. B. Wheeler Mitochondrial Functional State in Clonal Pancreatic {beta}-Cells Exposed to Free Fatty Acids J. Biol. Chem., May 23, 2003; 278(22): 19709 - 19715. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. A Schonfeld-Warden and C. H Warden Reply to R Cooper and A Luke Am. J. Clinical Nutrition, March 1, 2003; 77(3): 752 - 753. [Full Text]
|
|
|
|
|
|
H. Pilegaard, B. Saltin, and P. D. Neufer Effect of Short-Term Fasting and Refeeding on Transcriptional Regulation of Metabolic Genes in Human Skeletal Muscle Diabetes, March 1, 2003; 52(3): 657 - 662. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. S. Neitzel, A. N. Carley, and D. L. Severson Chylomicron and palmitate metabolism by perfused hearts from diabetic mice Am J Physiol Endocrinol Metab, February 1, 2003; 284(2): E357 - E365. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. S. Echtay, M. P. Murphy, R. A. J. Smith, D. A. Talbot, and M. D. Brand Superoxide Activates Mitochondrial Uncoupling Protein 2 from the Matrix Side. STUDIES USING TARGETED ANTIOXIDANTS J. Biol. Chem., November 27, 2002; 277(49): 47129 - 47135. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Calsbeek, T. L. Thompson, J. A. Dahl, N. R. Stob, J. T. Brozinick Jr., J. O. Hill, and M. S. Hickey Metabolic and anthropometric factors related to skeletal muscle UCP3 gene expression in healthy human adults Am J Physiol Endocrinol Metab, October 1, 2002; 283(4): E631 - E637. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. Zaninovich, M. Raices, I. Rebagliati, C. Ricci, and K. Hagmuller Brown fat thermogenesis in cold-acclimated rats is not abolished by the suppression of thyroid function Am J Physiol Endocrinol Metab, September 1, 2002; 283(3): E496 - E502. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-E. Harper, R. Dent, S. Monemdjou, V. Bezaire, L. Van Wyck, G. Wells, G. N. Kavaslar, A. Gauthier, F. Tesson, and R. McPherson Decreased Mitochondrial Proton Leak and Reduced Expression of Uncoupling Protein 3 in Skeletal Muscle of Obese Diet-Resistant Women Diabetes, August 1, 2002; 51(8): 2459 - 2466. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Schrauwen and M. Hesselink UCP2 and UCP3 in muscle controlling body metabolism J. Exp. Biol., August 1, 2002; 205(15): 2275 - 2285. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. KOPECKY, P. FLACHS, K. BARDOVA, P. BRAUNER, T. PRAZAK, and J. SPONAROVA Modulation of Lipid Metabolism by Energy Status of Adipocytes: Implications for Insulin Sensitivity Ann. N.Y. Acad. Sci., June 1, 2002; 967(1): 88 - 101. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. WANG, M. A. CAWTHORNE, and J. C. CLAPHAM Enhanced Diabetogenic Effect of Streptozotocin in Mice Overexpressing UCP-3 in Skeletal Muscle Ann. N.Y. Acad. Sci., June 1, 2002; 967(1): 112 - 119. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Argyropoulos and M.-E. Harper Molecular Biology of Thermoregulation: Invited Review: Uncoupling proteins and thermoregulation J Appl Physiol, May 1, 2002; 92(5): 2187 - 2198. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Bezaire, W. Hofmann, J. K. G. Kramer, L. P. Kozak, and M.-E. Harper Effects of fasting on muscle mitochondrial energetics and fatty acid metabolism in Ucp3(-/-) and wild-type mice Am J Physiol Endocrinol Metab, November 1, 2001; 281(5): E975 - E982. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
