Hostname: page-component-586b7cd67f-2brh9 Total loading time: 0 Render date: 2024-11-22T22:45:48.393Z Has data issue: false hasContentIssue false
  • English
  • Français

The role of uncoupling protein 3 in fatty acid metabolism: protection against lipotoxicity?

Published online by Cambridge University Press:  05 March 2007

Patrick Schrauwen
Patrick Schrauwen*
Affiliation:
Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Departments of Human Biology and Movement Sciences, Maastricht University, PO Box 616, 6200 MD, Maastricht, The Netherlands
*
*Corresponding author: Dr P. Schrauwen Fax: +31 43 3670976, Email: [email protected]
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

The physiological function of the mitochondrial uncoupling protein (UCP), UCP3, is still under debate. There is, however, ample evidence to indicate that, in contrast to UCP1, the primary function of UCP3 is not the dissipation of energy. Rather, several lines of evidence suggest that UCP3 is associated with cellular fatty acid metabolism. The highest levels of expression of UCP3 have been found in type 2 glycolytic muscle fibres, and fasting and high-fat diets up regulate UCP3. This up-regulation is most pronounced in muscle with a low fat oxidative capacity. Acute exercise also up regulates UCP3, and this effect has been shown to be a result of the exercise-induced increase in plasma fatty acid levels. In contrast, regular physical activity, which increases fat oxidative capacity, reduces UCP3 content. Based on these data it has been postulated that UCP3 functions to export those fatty acids that cannot be oxidized from the mitochondrial matrix, in order to prevent fatty acid accumulation inside the matrix. Several experiments have been conducted to test this hypothesis. Blocking carnitine palmitoyltransferase 1, thereby reducing fat oxidative capacity, rapidly induces UCP3. High-fat diets, which increase the mitochondrial supply of fatty acids, also up regulate UCP. However, feeding a similar amount of medium-chain fatty acids, which can be oxidized inside the mitochondrial matrix and therefore does not need to be exported from the matrix, does not affect UCP3 protein levels. In addition, UCP3 is increased in patients with defective β-oxidation and is reduced after restoring oxidative capacity. In conclusion, it is suggested that UCP3 has an important physiological function in facilitating outward transport from the mitochondrial matrix of fatty acid anions that cannot be oxidized, thereby protecting against lipid-induced mitochondrial damage.

Keywords

Uncoupling protein 3LipotoxicityFatty acid metabolism
Type
Symposium 3: Mechanisms involved in exercise-induced mitochondrila biogenesis in skeletal muscle
Information
Proceedings of the Nutrition Society , Volume 63 , Issue 2 , May 2004 , pp. 287 - 292
Copyright
Copyright © The Nutrition Society 2004

References

Argyropoulos, G, Brown, AM, Willi, SM, Zhu, J, He, Y, Reitman, M, Geveo, SM, Spruill, I & Garvey, WT (1998) Effects of mutations in the human uncoupling protein 3 gene on the respiratory quotient and fat oxidation in severe obesity and type 2 diabetes. Journal of Clinical Investigation 102, 1345–1351.CrossRefGoogle ScholarPubMed
Bezaire, V, Hofmann, W, Kramer, JK, Kozak, LP & Harper, ME (2001) Effects of fasting on muscle mitochondrial energetics and fatty acid metabolism in Ucp3(-/-) and wild-type mice. American Journal of Physiology 281, E975–E982.Google ScholarPubMed
Boss, O, Samec, S, Desplanches, D, Mayet, M-H, Seydoux, J, Muzzin, P & Giacobino, J-P (1998) Effect of endurance training on mRNA expression of uncoupling proteins 1, 2 and 3 in the rat. FASEB Journal 12, 335–339.CrossRefGoogle Scholar
Boss, O, Samec, S, Paoloni-Giacobino, A, Rossier, C, Dulloo, A, Seydoux, J, Muzzin, P & Giacobino, J-P (1997) Uncoupling protein-3: a new member of the mitochondrial carrier family with tissue-specific expression. FEBS Letters 408, 39–42.CrossRefGoogle ScholarPubMed
Brand, MD, Pamplona, R, Portero-Otin, M, Requena, JR, Roebuck, SJ, Buckingham, JA, Clapham, JC & Cadenas, S (2002) Oxidative damage and phospholipid fatty acyl composition in skeletal muscle mitochondria from mice underexpressing or overexpressing uncoupling protein 3. Biochemical Journal 368, 597–603.CrossRefGoogle ScholarPubMed
Cortright, RN, Zheng, D, Jones, JP, Fluckey, JD, DiCarlo, SE, Grujic, D, Lowell, BB & Dohm, GL (1999) Regulation of skeletal muscle UCP-2 and UCP-3 gene expression by exercise and denervation. American Journal of Physiology 276, E217–E221.Google ScholarPubMed
Fleury, C, Neverova, M, Collins, S, Raimbault, S, Champigny, O, Levi-Meyrueis, C, Bouillaud, F, Seldin, MF, Surwit, RS, Ricquier, D & Warden, CH (1997) Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia. Nature Genetics 15, 269–273.CrossRefGoogle ScholarPubMed
Goglia, F & Skulachev, VP (2003) A function for novel uncoupling proteins: antioxidant defense of mitochondrial matrix by translocating fatty acid peroxides from the inner to the outer membrane leaflet. FASEB Journal 17, 1585–1591.CrossRefGoogle Scholar
Gong, DW, Monemdjou, S, Gavrilova, O, Leon, LR, Marcus-Samuels, B, Chou, CJ, Everett, C, Kozak, LP, Li, C, Deng, C, Harper, ME & Reitman, ML (2000) Lack of obesity and normal response to fasting and thyroid hormone in mice lacking uncoupling protein-3. Journal of Biological Chemistry 275, 16251–16257.CrossRefGoogle ScholarPubMed
Hesselink, MKC, Greenhaff, PL, Constantin-Teodosiu, D, Hultman, E, Saris, WHM, Nieuwlaat, R, Schaart, G, Kornips, E & Schrauwen, P (2003) Increased uncoupling protein 3 content does not affect mitochondrial function in human skeletal muscle in vivo. Journal of Clinical Investigation 111, 479–486.CrossRefGoogle Scholar
Hesselink, MKC, Keizer, HA, Borghouts, LB, Schaart, G, Kornips, CFP, Slieker, LJ, Sloop, KW, Saris, WHM & Schrauwen, P (2001) Protein expression of UCP3 differs between human type 1, type 2a and type 2b fibers. FASEB Journal 15, 10.1096/fj.1000–0517fje.CrossRefGoogle ScholarPubMed
Hidaka, S, Kakuma, T, Yoshimatsu, H, Sakino, H, Fukuchi, S & Sakata, T (1999) Streptozotocin treatment upregulates uncoupling protein 3 expression in the rat heart. Diabetes 48, 430–435.CrossRefGoogle ScholarPubMed
Kelley, DE, He, J, Menshikova, EV & Ritov, VB (2002) Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 51, 2944–2950.CrossRefGoogle ScholarPubMed
Kelley, DE & Mandarino, LJ (2000) Fuel selection in human skeletal muscle in insulin resistance: a reexamination. Diabetes 49, 677–683.CrossRefGoogle ScholarPubMed
Liang, P, Hughes, V & Fukagawa, NK (1997) Increased prevalence of mitochondrial DNA deletions in skeletal muscle of older individuals with impaired glucose tolerance: possible marker of glycemic stress. Diabetes 46, 920–923.CrossRefGoogle ScholarPubMed
Listenberger, LL, Han, X, Lewis, SE, Cases, S, Farese, RV Jr, Ory, DS & Schaffer, JE (2003) Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proceedings of the National Academy of Sciences USA 100, 3077–3082.CrossRefGoogle ScholarPubMed
Millet, L, Vidal, H, Andreelli, F, Larrouy, D, Riou, J-P, Ricquier, D, Laville, M & Langin, D (1997) Increased uncoupling protein-2 and -3 mRNA expression during fasting in obese and lean humans. Journal of Clinical Investigation 100, 2665–2670.CrossRefGoogle ScholarPubMed
Pilegaard, H, Ordway, GA, Saltin, B & Neufer, PD (2000) Transcriptional regulation of gene expression in human skeletal muscle during recovery from exercise. American Journal of Physiology 279, E806–E814.Google ScholarPubMed
Russell, AP, Schrauwen, P, Somm, E, Gastaldi, G, Hesselink, MKC, Schaart, G, Kornips, E, Lo, SK, Bufano, D, Giacobino, J-P, Muzzin, P, Ceccon, M, Angelini, C & Vergani, L (2003 a) Decreased fatty acid β-oxidation in riboflavin-responsive multiple acylCoA dehydrogenase deficient patients is associated with an increase in UCP3. Journal of Clinical Endocrinology and Metabolism 88, 5921–5926.CrossRefGoogle Scholar
Russell, AP, Wadley, G, Hesselink, MKC, Schaart, G, Lo, S, Leger, B, Garnham, A, Kornips, E, Cameron-Smith, D, Giacobino, JP, Muzzin, P, Snow, R & Schrauwen, P (2003 b) UCP3 protein expression is lower in type I, IIa and IIx muscle fiber types of endurance-trained compared to untrained subjects. Pflugers Archiv European Journal of Physiology 445, 563–569.CrossRefGoogle ScholarPubMed
Samec, S, Seydoux, J & Dulloo, AG (1998) Role of UCP homologues in skeletal muscles and brown adipose tissue: mediators of thermogenesis or regulators of lipids as fuel substrate. FASEB Journal 12, 715–724.CrossRefGoogle ScholarPubMed
Schrauwen, P & Hesselink, M (2003) Uncoupling protein 3 and physical activity: the role of uncoupling protein 3 in energy metabolism revisited. Proceedings of the Nutrition Society 62, 635–643.CrossRefGoogle ScholarPubMed
Schrauwen, P, Hesselink, MK, Blaak, EE, Borghouts, LB, Schaart, G, Saris, WH, Keizer, HA, (2001 a) Uncoupling protein 3 content is decreased in skeletal muscle of patients with type 2 diabetes. Diabetes 50, 2870–2873.CrossRefGoogle ScholarPubMed
Schrauwen, P, Hesselink, MK, Vaartjes, I, Kornips, E, Saris, WH, Giacobino, JP & Russell, A (2002 a) Effect of acute exercise on uncoupling protein 3 is a fat metabolism-mediated effect. American Journal of Physiology 282, E11–E17.Google ScholarPubMed
Schrauwen, P, Hinderling, V, Hesselink, MKC, Schaart, G, Kornips, E, Saris, WHM, Westerterp-Plantega, M & Langhans, W (2002 b) Etomoxir-induced increase in UCP3 supports a role of uncoupling protein 3 as a mitochondrial fatty acid anion exporter. FASEB Journal 16, 10.1096/fj.1002–0275fje.CrossRefGoogle ScholarPubMed
Schrauwen, P, Hoeks, J, Schaart, G, Kornips, E, Binas, B, Vusse, GJvd, Bilsen, Mv, Luiken, JJFP, Coort, SLM, Glatz, JFC, Saris, WHM & Hesselink, MKC (2003) Uncoupling protein 3 as a mitochondrial fatty acid anion exporter. FASEB Journal 17, 2272–2274.CrossRefGoogle ScholarPubMed
Schrauwen, P, Hoppeler, H, Billeter, R, Bakker, AH & Pendergast, DR (2001 b) Fiber type dependent upregulation of human skeletal muscle UCP2 and UCP3 mRNA expression by high-fat diet. International Journal of Obesity and Related Metabolic Disorders 25, 449–456.CrossRefGoogle ScholarPubMed
Schrauwen, P, Saris, WH & Hesselink, MK (2001 c) An alternative function for human uncoupling protein 3: protection of mitochondria against accumulation of nonesterified fatty acids inside the mitochondrial matrix. FASEB Journal 15, 2497–2502.CrossRefGoogle ScholarPubMed
Skulachev, VP (1999) Anion carriers in fatty acid-mediated physiological uncoupling. Journal of Bioenergetics and Biomembranes 31, 431–445.CrossRefGoogle ScholarPubMed
Tsuboyama-Kasaoka, N, Tsunoda, N, Maruyama, K, Takahashi, M, Kim, H, Ikemoto, S & Ezaki, O (1998) Up-regulation of uncoupling protein 3 (UCP3) mRNA by exercise training and down-regulation of UCP3 by denervation in skeletal muscles. Biochemical and Biophysical Research Communications 247, 498–503.CrossRefGoogle ScholarPubMed
Weigle, DS, Selfridge, LE, Schwartz, MW, Seeley, RJ, Cummings, DE, Havel, PJ, Kuijper, JL & BertrandelRio, H (1998) Elevated free fatty acids induce uncoupling protein 3 expression in muscle. A potential explanation for the effect of fasting. Diabetes 47, 298–302.CrossRefGoogle ScholarPubMed