Abstract
Long-chain (C16-C20) fatty acids, which are stored in adipose tissue, can be β-oxidised for the production of energy. The main part of the β-oxidation takes place in the mitochondria, a small part of the fatty acids is metabolised in the peroxisomes. Energy production from fatty acids becomes crucial during prolonged fasting. It has been known for a long time that the fasting brain depends on two fuels, i.e. glucose derived from gluconeogenesis and ketone bodies derived from mitochondrial fatty acid β-oxidation. Both processes mainly reside in the liver. Entry of the long-chain fatty acids into the mitochondrion requires the formation of fatty acyl carnitine esters by carnitine palmitoyltransferase 1 (CPT1) at the mitochondrial outer membrane (Fig. 1). The carnitine esters are then shuttled across the inner membrane by the carnitine acylcarnitine carrier protein (CAC). Attached to the inner side of the inner mitochondrial membrane are three proteins with all together five enzyme activities, i.e. carnitine palmitoyltransferase 2 (CPT2), very long-chain acyl-CoA dehydrogenase (VLCAD) and the so-called mitochondrial trifunctional protein (MTP) with long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), long-chain enoyl-CoA hydratase and long-chain 3-oxothiolase activities. Although there is no hard evidence yet, it is likely that there is channeling of substrates between these proteins.
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References
Nezu J, Tamai I, Oku A, Ohashi R, Yabuuchi H, Hashimoto N et al. Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium iondependent carnitine transporter. Nat Genet 1999;21:91–94.
Hilst L, Mandel H, Oostheim W, Ruiter JP, Gutman A, Wanders RJ. Molecular basis of hepatic carnitine palmitoyltransferase I deficiency. J Clin Invest 1998;102:527–531.
Innes AM, Seargeant LE, Balachandra K, Roe CR, Wanders RJ, Ruiter JP et al. Hepatic carnitine palmitoyltransferase I deficiency presenting as maternal illness in pregnancy. Pediatr Res 2000;47:43–45.
Roschinger W, Muntau AC, Duran M, Dorland L, IJlst L, Wanders RJ et al. Carnitine-acylcarnitine translocase deficiency: metabolic consequences of an impaired mitochondrial carnitine cycle. Clin Chim Acta 2000;298:55–68.
Bonnefont JP, Taroni F, Cavadini P, Cepanec C, Brivet M, Saudubray JM et al. Molecular analysis of carnitine palmitoyltransferase II deficiency with hepatocardiomuscular expression. Am J Hum Genet 1996;58:971–978.
Vianey-Saban C, Divry P, Brivet M, Nada M, Zabot MT, Mathieu M et al. Mitochondrial very-long-chain acyl-coenzyme A dehydrogenase deficiency: clinical characteristics and diagnostic considerations in 30 patients. Clin Chim Acta 1998;269:43–62.
Tanaka K, Gregersen N, Ribes A, Kim J, Kolvraa S, Winter V et al. A survey of the newborn populations in Belgium, Germany, Poland, Czech Republic, Hungary, Bulgaria, Spain, Turkey, and Japan for the G985 variant allele with haplotype analysis at the medium chain acyl-CoA dehydrogenase gene locus: clinical and evolutionary consideration. Pediatr Res 1997;41:201–209.
Corydon MJ, Vockley J, Rinaldo P, Rhead WJ, Kjeldsen M, Winter V et al. Role of common gene variations in the molecular pathogenesis of short-chain acyl-CoA dehydrogenase deficiency. Pediatr Res 2001;49:18–23.
Burlina AB, Dionisi-Vici C, Bennett MJ, Gibson KM, Servidei S, Bertini E et al. A new syndrome with ethylmalonic aciduria and normal fatty acid oxidation in fibroblasts. J Pediatr 1994;124:79–86.
IJlst L, Wanders RJ, Ushikubo S, Kamijo T, Hashimoto T. Molecular basis of longchain 3-hydroxyacyl-CoA dehydrogenase deficiency: identification of the major disease-causing mutation in the alpha-subunit of the mitochondrial trifunctional protein. Biochim Biophys Acta 1994;1215:347–350.
Kamijo T, Wanders RJ, Saudubray JM, Aoyama T, Komiyama A, Hashimoto T. Mitochondrial trifunctional protein deficiency. Catalytic heterogeneity of the mutant enzyme in two patients. J Clin Invest 1994;93:1740–1747.
Treem WR, Rinaldo P, Hale DE, Stanley CA, Millington DS, Hyams JS et al. Acute fatty liver of pregnancy and long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency. Hepatology 1994;19:339–345.
Bennett MJ, Spotswood SD, Ross KF, Comfort S, Koonce R, Boriack RL et al. Fatal hepatic short-chain L-3-hydroxyacyl-coenzyme A dehydrogenase deficiency: clinical, biochemical, and pathological studies on three subjects with this recently identified disorder of mitochondrial beta-oxidation. Pediatr Dev Pathol 1999;2:337–345.
Rhead WJ, Wolff JA, Lipson M, Falace P, Desai N, Fritchman K et al. Clinical and biochemical variation and family studies in the multiple acyl-CoA dehydrogenation disorders. Pediatr Res 1987;21:371–376.
Antozzi C, Garavaglia B, Mora M, Rimoldi M, Morandi L, Ursino E et al. Late-onset riboflavin-responsive myopathy with combined multiple acyl coenzyme A dehydrogenase and respiratory chain deficiency. Neurology 1994;44:2153–2158.
Thompson GN, Hsu BY, Pitt JJ, Treacy E, Stanley CA. Fasting hypoketotic coma in a child with deficiency of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase. N Engl J Med 1997;337:1203–1207.
Fukao T, Mitchell GA, Song XQ, Nakamura H, Kassovska-Bratinova S, Orii KE et al. Succinyl-CoA:3-ketoacid CoA transferase (SCOT): cloning of the human SCOT gene, tertiary structural modeling of the human SCOT monomer, and characterization of three pathogenic mutations. Genomics 2000;68:144–151.
Costa CC, De Almeida IT, Jakobs C, Poll-The BT, Duran M. Dynamic changes of plasma acylcarnitine levels induced by fasting and sunflower oil challenge test in children. Pediatr Res 1999;46:440–444.
Bonnefont JP, Specola NB, Vassault A, Lombes A, Ogier H, de Klerk JBC et al. The fasting test in paediatrics: application to the diagnosis of pathological. Eur J Pediatr 1990;150:80–85.
Seakins JW, Rumsby G. The use of phenylpropionic acid as a loading test for medium-chain acyl-CoA dehydrogenase deficiency. J Inherit Metab Dis 1988;11 Suppl 2:221–224.
Morris AA, Lascelles CV, Olpin SE, Lake BD, Leonard JV, Quant PA. Hepatic mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase deficiency. Pediatr Res 1998;44:392–396.
Brivet M, Slama A, Saudubray JM, Legrand A, Lemonnier A. Rapid diagnosis of long chain and medium chain fatty acid oxidation disorders using lymphocytes. Ann Clin Biochem 1995;32:154–159.
Ventura FV, Costa CG, Struys EA, Ruiter J, Allers P, Hilst L et al. Quantitative acylcarnitine profiling in fibroblasts using [U-13C] palmitic acid: an improved tool for the diagnosis of fatty acid oxidation defects. Clin Chim Acta 1999;281:1–17.
Costa CG, Dorland L, Holwerda U, Tavares de Almeida I, Poll-The BT, Jakobs C et al. Simultaneous analysis of plasma free fatty acids and their 3-hydroxy analogs in fatty acid beta-oxidation disorders. Clin Chem 1998;44:463–471.
Kamijo T, Indo Y, Souri M, Aoyama T, Hara T, Yamamoto S et al. Medium chain 3-ketoacyl-coenzyme A thiolase deficiency: a new disorder of mitochondrial fatty acid beta-oxidation. Pediatr Res 1997;42:569–576.
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Duran, M. (2003). Disorders of Mitochondrial Fatty Acid Oxidation and Ketone Body Handling. In: Blau, N., Duran, M., Blaskovics, M.E., Gibson, K.M. (eds) Physician’s Guide to the Laboratory Diagnosis of Metabolic Diseases. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-55878-8_20
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DOI: https://doi.org/10.1007/978-3-642-55878-8_20
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