- Reuter, S. E. & Evans, A. M. Carnitine and acylcarnitines: pharmacokinetic, pharmacological and clinical aspects. Clin. Pharmacokinet. 51, 553–572 (2012).
Article CAS PubMed Google Scholar
- Rinaldo, P., Matern, D. & Bennett, M. J. Fatty acid oxidation disorders. Annu. Rev. Physiol. 64, 477–502 (2002).
Article CAS PubMed Google Scholar
- Wilcken, B., Wiley, V., Hammond, J. & Carpenter, K. Screening newborns for inborn errors of metabolism by tandem mass spectrometry. N. Engl. J. Med. 348, 2304–2312 (2003).
Article CAS PubMed Google Scholar
- Rocha, H. et al. Birth prevalence of fatty acid β-oxidation disorders in Iberia. JIMD Rep. 16, 89–94 (2014).
Article PubMed PubMed Central Google Scholar
- Brass, E. P. & Hoppel, C. L. Relationship between acid-soluble carnitine and coenzyme A pools in vivo. Biochem J. 190, 495–504 (1980).
Article CAS PubMed PubMed Central Google Scholar
- Ramsay, R. R. & Zammit, V. A. Carnitine acyltransferases and their influence on CoA pools in health and disease. Mol. Aspects Med. 25, 475–493 (2004).
Article CAS PubMed Google Scholar
- Eaton, S., Bartlett, K. & Pourfarzam, M. Mammalian mitochondrial β-oxidation. Biochem J. 320, 345–357 (1996).
Article CAS PubMed PubMed Central Google Scholar
- Noland, R. C. et al. Carnitine insufficiency caused by aging and overnutrition compromises mitochondrial performance and metabolic control. J. Biol. Chem. 284, 22840–22852 (2009).
Article CAS PubMed PubMed Central Google Scholar
- Violante, S. et al. Carnitine palmitoyltransferase 2 and carnitine/acylcarnitine translocase are involved in the mitochondrial synthesis and export of acylcarnitines. FASEB J. 27, 2039–2044 (2013).
Article CAS PubMed Google Scholar
- Palmieri, F. The mitochondrial transporter family SLC25: identification, properties and physiopathology. Mol. Aspects Med. 34, 465–484 (2013).
Article CAS PubMed Google Scholar
- Pochini, L., Oppedisano, F. & Indiveri, C. Reconstitution into liposomes and functional characterization of the carnitine transporter from renal cell plasma membrane. Biochim. Biophys. Acta 1661, 78–86 (2004).
Article CAS PubMed Google Scholar
- Suhre, K. et al. Human metabolic individuality in biomedical and pharmaceutical research. Nature 477, 54–60 (2011).
Article CAS PubMed Google Scholar
- Hediger, M. A. et al. The ABCs of solute carriers: physiological, pathological and therapeutic implications of human membrane transport proteins. Pflugers Arch. 447, 465–468 (2004).
Article CAS PubMed Google Scholar
- He, L., Vasiliou, K. & Nebert, D. W. Analysis and update of the human solute carrier (SLC) gene superfamily. Hum. Genomics 3, 195–206 (2009).
Article CAS PubMed PubMed Central Google Scholar
- Carpenter, K. H. & Wiley, V. Application of tandem mass spectrometry to biochemical genetics and newborn screening. Clin. Chim. Acta 322, 1–10 (2002).
Article CAS PubMed Google Scholar
- Rinaldo, P., Cowan, T. M. & Matern, D. Acylcarnitine profile analysis. Genet. Med. 10, 151–156 (2008).
Article PubMed Google Scholar
- Bonnefont, J. P. et al. Carnitine palmitoyltransferase deficiencies. Mol. Genet. Metab. 68, 424–440 (1999).
Article CAS PubMed Google Scholar
- Matern, D. & Rinaldo, P. in GeneReviews ®(eds Pagon, R. A. et al.) Medium-chain acyl-coenzyme A dehydrogenase deficiency (University of Washington, 1993).
Google Scholar
- Spiekerkoetter, U. Mitochondrial fatty acid oxidation disorders: clinical presentation of long-chain fatty acid oxidation defects before and after newborn screening. J. Inherit. Metab. Dis. 33, 527–532 (2010).
Article CAS PubMed Google Scholar
- Stanley, C. A. et al. A deficiency of carnitine–acylcarnitine translocase in the inner mitochondrial membrane. N. Engl. J. Med. 327, 19–23 (1992).
Article CAS PubMed Google Scholar
- Schiff, M. et al. Molecular and cellular pathology of very-long-chain acyl-CoA dehydrogenase deficiency. Mol. Genet. Metab. 109, 21–27 (2013).
Article CAS PubMed PubMed Central Google Scholar
- Rector, R. S., Payne, R. M. & Ibdah, J. A. Mitochondrial trifunctional protein defects: clinical implications and therapeutic approaches. Adv. Drug Deliv. Rev. 60, 1488–1496 (2008).
Article CAS PubMed PubMed Central Google Scholar
- Isackson, P. J. et al. CPT2 gene mutations resulting in lethal neonatal or severe infantile carnitine palmitoyltransferase II deficiency. Mol. Genet. Metab. 94, 422–427 (2008).
Article CAS PubMed Google Scholar
- McHugh, D. et al. Clinical validation of cutoff target ranges in newborn screening of metabolic disorders by tandem mass spectrometry: a worldwide collaborative project. Genet. Med. 13, 230–254 (2011).
Article PubMed Google Scholar
- Pollitt, R. J. Disorders of mitochondrial long-chain fatty acid oxidation. J. Inherit. Metab. Dis. 18, 473–490 (1995).
Article CAS PubMed Google Scholar
- Gillingham, M. B. et al. Optimal dietary therapy of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Mol. Genet. Metab. 79, 114–123 (2003).
Article CAS PubMed PubMed Central Google Scholar
- Schiff, M., Bénit, P., Jacobs, H. T., Vockley, J. & Rustin, P. Therapies in inborn errors of oxidative metabolism. Trends Endocrinol. Metab. 23, 488–495 (2012).
Article CAS PubMed PubMed Central Google Scholar
- Knabb, M. T., Saffitz, J. E., Corr, P. B. & Sobel, B. E. The dependence of electrophysiological derangements on accumulation of endogenous long-chain acyl carnitine in hypoxic neonatal rat myocytes. Circ. Res. 58, 230–240 (1986).
Article CAS PubMed Google Scholar
- Sato, T., Kiyosue, T. & Arita, M. Inhibitory effects of palmitoylcarnitine and lysophosphatidylcholine on the sodium current of cardiac ventricular cells. Pflugers Arch. 420, 94–100 (1992).
Article CAS PubMed Google Scholar
- Aguer, C. et al. Acylcarnitines: potential implications for skeletal muscle insulin resistance. FASEB J. 29, 336–345 (2015).
Article CAS PubMed Google Scholar
- Rutkowsky, J. M. et al. Acylcarnitines activate proinflammatory signaling pathways. Am. J. Physiol. Endocrinol. Metab. 306, E1378–E1387 (2014).
Article CAS PubMed PubMed Central Google Scholar
- McCoin, C. S., Knotts, T. A., Ono-Moore, K. D., Oort, P. J. & Adams, S. H. Long-chain acylcarnitines activate cell stress and myokine release in C2C12 myotubes: calcium-dependent and -independent effects. Am. J. Physiol. Endocrinol. Metab. 308, E990–E1000 (2015).
Article PubMed PubMed Central CAS Google Scholar
- Sobiesiak-Mirska, J. & A. Nałecz, K. Palmitoylcarnitine modulates interaction between protein kinase C βII and its receptor RACK1. FEBS J. 273, 1300–1311 (2006).
Article CAS PubMed Google Scholar
- Lopaschuk, G. D., Ussher, J. R., Folmes, C. D., Jaswal, J. S. & Stanley, W. C. Myocardial fatty acid metabolism in health and disease. Physiol. Rev. 90, 207–258 (2010).
Article CAS PubMed Google Scholar
- Lopaschuk, G. D., Wall, S. R., Olley, P. M. & Davies, N. J. Etomoxir, a carnitine palmitoyltransferase I inhibitor, protects hearts from fatty acid-induced ischemic injury independent of changes in long chain acylcarnitine. Circ. Res. 63, 1036–1043 (1988).
Article CAS PubMed Google Scholar
- Heathers, G. P., Yamada, K. A., Kanter, E. M. & Corr, P. B. Long-chain acylcarnitines mediate the hypoxia-induced increase in α1-adrenergic receptors on adult canine myocytes. Circ. Res. 61, 735–746 (1987).
Article CAS PubMed Google Scholar
- Corr, P. B., Creer, M. H., Yamada, K. A., Saffitz, J. E. & Sobel, B. E. Prophylaxis of early ventricular fibrillation by inhibition of acylcarnitine accumulation. J. Clin. Invest. 83, 927–936 (1989).
Article CAS PubMed PubMed Central Google Scholar
- Cho, K. S. & Proulx, P. Lysis of erythrocytes by long-chain acyl esters of carnitine. Biochim. Biophys. Acta 193, 30–35 (1969).
Article CAS PubMed Google Scholar
- Busselen, P., Sercu, D. & Verdonck, F. Exogenous palmitoyl carnitine and membrane damage in rat hearts. J. Mol. Cell. Cardiol. 20, 905–916 (1988).
Article CAS PubMed Google Scholar
- Xiao, C. Y., Chen, M., Hara, A., Hashizume, H. & Abiko, Y. Palmitoyl-L-carnitine modifies the myocardial levels of high-energy phosphates and free fatty acids. Basic Res. Cardiol. 92, 320–330 (1997).
Article CAS PubMed Google Scholar
- Adams, R. J. et al. In vitro effects of palmitylcarnitine on cardiac plasma membrane Na, K-ATPase, and sarcoplasmic reticulum Ca2+-ATPase and Ca2+ transport. J. Biol. Chem. 254, 12404–12410 (1979).
Article CAS PubMed Google Scholar
- Wu, J. & Corr, P. B. Palmitoylcarnitine increases [Na+]i and initiates transient inward current in adult ventricular myocytes. Am. J. Physiol. 268, H2405–H2417 (1995).
CAS PubMed Google Scholar
- Meszaros, J. & Pappano, A. J. Electrophysiological effects of L-palmitoylcarnitine in single ventricular myocytes. Am. J. Physiol. 258, H931–H938 (1990).
CAS PubMed Google Scholar
- Lamers, J. M., Stinis, H. T., Montfoort, A. & Hulsmann, W. C. The effect of lipid intermediates on Ca2+ and Na+ permeability and (Na+ + K+)-ATPase of cardiac sarcolemma. A possible role in myocardial ischemia. Biochim. Biophys. Acta 774, 127–137 (1984).
Article CAS PubMed Google Scholar
- Yamada, K. A., Kanter, E. M. & Newatia, A. Long-chain acylcarnitine induces Ca2+ efflux from the sarcoplasmic reticulum. J. Cardiovasc. Pharmacol. 36, 14–21 (2000).
Article CAS PubMed Google Scholar
- Wood, J. M., Bush, B., Pitts, B. J. & Schwartz, A. Inhibition of bovine heart Na+, K+-ATPase by palmitylcarnitine and palmityl-CoA. Biochem. Biophys. Res. Commun. 74, 677–684 (1977).
Article CAS PubMed Google Scholar
- el-Hayek, R., Valdivia, C., Valdivia, H. H., Hogan, K. & Coronado, R. Activation of the Ca2+ release channel of skeletal muscle sarcoplasmic reticulum by palmitoyl carnitine. Biophys. J. 65, 779–789 (1993).
Article CAS PubMed PubMed Central Google Scholar
- Wu, J., McHowat, J., Saffitz, J. E., Yamada, K. A. & Corr, P. B. Inhibition of gap junctional conductance by long-chain acylcarnitines and their preferential accumulation in junctional sarcolemma during hypoxia. Circ. Res. 72, 879–889 (1993).
Article CAS PubMed Google Scholar
- Sato, T., Arita, M. & Kiyosue, T. Differential mechanism of block of palmitoyl lysophosphatidylcholine and of palmitoylcarnitine on inward rectifier K+ channels of guinea-pig ventricular myocytes. Cardiovasc. Drugs Ther. 7 (Suppl. 3), 575–584 (1993).
Article PubMed Google Scholar
- Ferro, F. et al. Long-chain acylcarnitines regulate the hERG channel. PLoS ONE 7, e41686 (2012).
Article CAS PubMed PubMed Central Google Scholar
- Liu, Q. Y. & Rosenberg, R. L. Activation and inhibition of reconstituted cardiac L-type calcium channels by palmitoyl-L-carnitine. Biochem. Biophys. Res. Commun. 228, 252–258 (1996).
Article CAS PubMed Google Scholar
- Wu, J. & Corr, P. B. Influence of long-chain acylcarnitines on voltage-dependent calcium current in adult ventricular myocytes. Am. J. Physiol. 263, H410–H417 (1992).
CAS PubMed Google Scholar
- De Villiers, M. & Lochner, A. Mitochondrial Ca2+ fluxes: role of free fatty acids, acyl-CoA and acylcarnitine. Biochim Biophys Acta 876, 309–317 (1986).
Article CAS PubMed Google Scholar
- Wolkowicz, P. E. & McMillin-Wood, J. Respiration-dependent calcium ion uptake by two preparations of cardiac mitochondria. Effects of palmitoyl-coenzyme A and palmitoylcarnitine on calcium ion cycling and nicotinamide nucleotide reduction state. Biochem. J. 186, 257–266 (1980).
Article CAS PubMed PubMed Central Google Scholar
- Baydoun, A. R., Markham, A., Morgan, R. M. & Sweetman, A. J. Palmitoyl carnitine: an endogenous promotor of calcium efflux from rat heart mitochondria. Biochem Pharmacol 37, 3103–3107 (1988).
Article CAS PubMed Google Scholar
- Hoppel, C. L. & Genuth, S. M. Carnitine metabolism in normal-weight and obese human subjects during fasting. Am. J. Physiol. 238, E409–E415 (1980).
CAS PubMed Google Scholar
- Adams, S. H. et al. Plasma acylcarnitine profiles suggest incomplete long-chain fatty acid β-oxidation and altered tricarboxylic acid cycle activity in type 2 diabetic African-American women. J. Nutr. 139, 1073–1081 (2009).
Article CAS PubMed PubMed Central Google Scholar
- Mai, M. et al. Serum levels of acylcarnitines are altered in prediabetic conditions. PLoS ONE 8, e82459 (2013).
Article PubMed PubMed Central CAS Google Scholar
- Ha, C. Y. et al. The association of specific metabolites of lipid metabolism with markers of oxidative stress, inflammation and arterial stiffness in men with newly diagnosed type 2 diabetes. Clin. Endocrinol. (Oxf.) 76, 674–682 (2012).
Article CAS Google Scholar
- Mihalik, S. J. et al. Increased levels of plasma acylcarnitines in obesity and type 2 diabetes and identification of a marker of glucolipotoxicity. Obesity (Silver Spring) 18, 1695–1700 (2010).
Article CAS Google Scholar
- Koves, T. R. et al. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab. 7, 45–56 (2008).
Article CAS PubMed Google Scholar
- Muoio, D. M. & Koves, T. R. Lipid-induced metabolic dysfunction in skeletal muscle. Novartis Found Symp. 286, 24–38 (2007).
Article CAS PubMed Google Scholar
- Itani, S. I., Ruderman, N. B., Schmieder, F. & Boden, G. Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IκB-α. Diabetes 51, 2005–2011 (2002).
Article CAS PubMed Google Scholar
- Holland, W. L. et al. Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell Metab. 5, 167–179 (2007).
Article CAS PubMed Google Scholar
- Hotamisligil, G. S., Shargill, N. S. & Spiegelman, B. M. Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin resistance. Science 259, 87–91 (1993).
Article CAS PubMed Google Scholar
- An, J. et al. Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resistance. Nat. Med. 10, 268–274 (2004).
Article CAS PubMed Google Scholar
- Koves, T. R. et al. Peroxisome proliferator-activated receptor-γ co-activator 1α-mediated metabolic remodeling of skeletal myocytes mimics exercise training and reverses lipid-induced mitochondrial inefficiency. J. Biol. Chem. 280, 33588–33598 (2005).
Article CAS PubMed Google Scholar
- Chao, L. C. et al. Insulin resistance and altered systemic glucose metabolism in mice lacking Nur77. Diabetes 58, 2788–2796 (2009).
Article CAS PubMed PubMed Central Google Scholar
- De Vogel-van den Bosch, J. et al. The effects of long- or medium-chain fat diets on glucose tolerance and myocellular content of lipid intermediates in rats. Obesity (Silver Spring) 19, 792–799 (2011).
Article CAS Google Scholar
- Wellen, K. E. & Hotamisligil, G. S. Inflammation, stress, and diabetes. J. Clin. Invest. 115, 1111–1119 (2005).
Article CAS PubMed PubMed Central Google Scholar
- Summers, S. A. Ceramides in insulin resistance and lipotoxicity. Prog. Lipid Res. 45, 42–72 (2006).
Article CAS PubMed Google Scholar
- Erion, D. M. & Shulman, G. I. Diacylglycerol-mediated insulin resistance. Nat. Med. 16, 400–402 (2010).
Article CAS PubMed PubMed Central Google Scholar
- Lee, J. Y., Sohn, K. H., Rhee, S. H. & Hwang, D. Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4. J. Biol. Chem. 276, 16683–16689 (2001).
Article CAS PubMed Google Scholar
- Lee, J. Y. et al. Saturated fatty acid activates but polyunsaturated fatty acid inhibits Toll-like receptor 2 dimerized with Toll-like receptor 6 or 1. J. Biol. Chem. 279, 16971–16979 (2004).
Article CAS PubMed Google Scholar
- Wong, S. W. et al. Fatty acids modulate Toll-like receptor 4 activation through regulation of receptor dimerization and recruitment into lipid rafts in a reactive oxygen species-dependent manner. J. Biol. Chem. 284, 27384–27392 (2009).
Article CAS PubMed PubMed Central Google Scholar
- Huang, S. et al. Saturated fatty acids activate TLR-mediated proinflammatory signaling pathways. J. Lipid Res. 53, 2002–2013 (2012).
Article CAS PubMed PubMed Central Google Scholar
- Sampey, B. P. et al. Metabolomic profiling reveals mitochondrial-derived lipid biomarkers that drive obesity-associated inflammation. PLoS ONE 7, e38812 (2012).
Article CAS PubMed PubMed Central Google Scholar
- Mutomba, M. C. et al. Regulation of the activity of caspases by L-carnitine and palmitoylcarnitine. FEBS Lett. 478, 19–25 (2000).
Article CAS PubMed Google Scholar
- Katoh, N., Wrenn, R. W., Wise, B. C., Shoji, M. & Kuo, J. F. Substrate proteins for calmodulin-sensitive and phospholipid-sensitive Ca2+-dependent protein kinases in heart, and inhibition of their phosphorylation by palmitoylcarnitine. Proc. Natl Acad. Sci. USA 78, 4813–4817 (1981).
Article CAS PubMed PubMed Central Google Scholar
- Requero, M. A., Gonzalez, M., Goni, F. M., Alonso, A. & Fidelio, G. Differential penetration of fatty acyl-coenzyme A and fatty acylcarnitines into phospholipid monolayers. FEBS Lett. 357, 75–78 (1995).
Article CAS PubMed Google Scholar
- Wise, B. C. et al. Phospholipid-sensitive Ca2+-dependent protein kinase from heart. II. Substrate specificity and inhibition by various agents. J. Biol. Chem. 257, 8489–8495 (1982).
Article CAS PubMed Google Scholar
- Nakadate, T. & Blumberg, P. M. Modulation by palmitoylcarnitine of protein kinase C activation. Cancer Res. 47, 6537–6542 (1987).
CAS PubMed Google Scholar
- Oh, S. Y., Madhukar, B. V. & Trosko, J. E. Inhibition of gap junctional blockage by palmitoyl carnitine and TMB-8 in a rat liver epithelial cell line. Carcinogenesis 9, 135–139 (1988).
Article CAS PubMed Google Scholar
- Moraru, II, Laky, M., Stanescu, T., Buzila, L. & Popescu, L. M. Protein kinase C controls Fcγ receptor-mediated endocytosis in human neutrophils. FEBS Lett. 274, 93–95 (1990).
Article CAS PubMed Google Scholar
- Nakaki, T., Mita, S., Yamamoto, S., Nakadate, T. & Kato, R. Inhibition by palmitoylcarnitine of adhesion and morphological changes in HL-60 cells induced by 12-O-tetradecanoylphorbol-13-acetate. Cancer Res. 44, 1908–1912 (1984).
CAS PubMed Google Scholar
- Nalecz, K. A., Mroczkowska, J. E., Berent, U. & Nalecz, M. J. Effect of palmitoylcarnitine on the cellular differentiation, proliferation and protein kinase C activity in neuroblastoma nb-2a cells. Acta Neurobiol. Exp. (Wars) 57, 263–274 (1997).
CAS Google Scholar
- Muoio, D. M. et al. Muscle-specific deletion of carnitine acetyltransferase compromises glucose tolerance and metabolic flexibility. Cell Metab. 15, 764–777 (2012).
Article CAS PubMed PubMed Central Google Scholar
- Schenkel, L. C. & Bakovic, M. Formation and regulation of mitochondrial membranes. Int. J. Cell Biol. 2014, 709828 (2014).
Article PubMed PubMed Central CAS Google Scholar
- Horvath, S. E. & Daum, G. Lipids of mitochondria. Prog. Lipid Res. 52, 590–614 (2013).
Article CAS PubMed Google Scholar
- Mochly-Rosen, D., Das, K. & Grimes, K. V. Protein kinase C, an elusive therapeutic target? Nat. Rev. Drug Discov. 11, 937–957 (2012).
Article CAS PubMed PubMed Central Google Scholar