Beatrice Morio, University of Texas Medical Branch, Galveston, Texas, USA
Catherine W Yeckel, University of Texas Medical Branch, Galveston, Texas, USA
Robert R Wolfe, University of Texas Medical Branch, Galveston, Texas, USA
Published online: May 2003
DOI: 10.1038/npg.els.0000633
The regulation of fatty acid oxidation is multifaceted, but the oxidation of fatty acids can only proceed once fatty acids gave gained entry to mitochondria. The mechanisms of transmembrane and transcellular movement of fatty acids may involve a number of fatty acid‐binding proteins. The gateway into mitochondria may be regulated by carnitine palmitoyltransferase.
Keywords: lipolysis; transport; carnitine transferases; malonyl‐CoA; β‐oxidation; ketogenesis
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Figure 1.
Schematic presentation of the uptake and utilization of long‐chain (LC) fatty acids (FA) by parenchymal cells, with emphasis on the assumed or proposed role of various lipid‐binding proteins in this process. See comments in text. Abbreviations: Chylo, chylomicrons; VLDL, very low‐density lipoproteins; Alb. BP, albumin‐binding protein; FABPpm, plasmalemmal fatty acid‐binding protein; FAT, fatty acid translocase (CD36); FATP, fatty acid transport protein; FABPc, cytoplasmic fatty acid‐binding protein; ACS, acyl‐CoA synthetase; ACBP, acyl‐CoA‐binding protein. Reproduced from Luiken JJ et al. (1999) Lipids34 (supplement): S169–S175, by permission of AOCS Press. |
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Figure 2.
Complex formed by carnitine palmitoyltransferases (CPT‐I and CPT‐II) at contact sites in the mitochondrial membranes for the transport of long‐chain fatty acids to the mitochondrial matrix. 1, Traditional representation of the association between CPT‐I, CPT‐II and carnitine acylcarnitine translocase (CACT). This theory suggests that the CPT‐I active site is located within the outer membrane (for more details see Park and Cook, ). 2, Recent evidence suggests that the CPT‐I active site faces the cytosol and that CACT is less expressed at contact sites and more uniformly distributed in the mitochondrial inner membrane, and therefore does not necessitate direct contact with CPT‐I and II (for more details see Zammit, ). Abbreviations: LCFA, long‐chain fatty acids; FABPc, cytoplasmic fatty acid‐binding protein; ACS, acyl‐CoA synthetase; LC acyl‐CoA, long‐chain acyl‐CoA; ACBP, acyl‐CoA‐binding protein. |
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Figure 3.
Location of various carnitine acyltransferases and proposed regulation of fatty acid channelling in the subcellular organelles of hepatocytes. (a) Fed state: glucose metabolism causes citrate to increase in the mitochondria, which ultimately causes malonyl‐CoA to increase, thereby inhibiting the activity of malonyl‐CoA‐sensitive carnitine palmitoyltransferases (CPT‐I, CPTo). Fatty acids cannot enter the subcellular organelles and are likely to be esterified into triacylglycerol (TAG) in the cytosol. Peroxisomal β‐oxidation is increased and/or more complete, probably owing to an inhibition of carnitine octanoyltransferase (COT) or through a still unknown process, which may involve the accumulation of long‐chain acyl‐CoA and dicarboxylic acids. (b) Fasted state: very long‐chain and long‐chain acyl‐CoA are transported into the subcellular organelles via the malonyl‐CoA‐sensitive carnitine palmitoyltransferases (CPT‐I, CPTo) for subsequent metabolism: β‐oxidation and ketogenesis in the mitochondria, β‐oxidation in the peroxisomes, TAG esterification in the endoplasmic reticulum. Abbreviations: VLC and LC‐acyl‐CoA, very long‐chain and long‐chain acyl‐CoA; ACBP, acyl‐CoA‐binding protein; CPT‐I and CPT‐II, carnitine palmitoyltransferases I and II; p‐CPTo, peroxisomal CPTo; m‐CPTo, microsomal CPTo; COT, carnitine octanoyltransferase; CPTm, microsomal CPT; CAT, carnitine acetyltransferase; TAG, triacylglycerol; TCA cycle, tricarboxylic acid cycle; ACC, acetyl‐CoA carboxylase; MCD, malonyl‐CoA decarboxylase. |
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Figure 4.
The β‐oxidation pathway of saturated acyl‐CoA in the mitochondria. |
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Figure 5.
The β‐oxidation pathway of unsaturated acyl‐CoA in the mitochondria. Linoleic acid is used as an example. |
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Figure 6.
The β‐oxidation pathway of saturated acyl‐CoA in the peroxisomes. |
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Figure 7.
The α‐oxidation pathway of phytanic acid (for more details see Wanders RJ (2000) Cell Biochemistry and Biophysics32: 89–106). |
References
Abo‐Hashema KA, Cake MH, Lukas MA and Knudsen J (1999) Evaluation of the affinity and turnover number of both hepatic mitochondrial and microsomal carnitine acyltransferases: relevance to intracellular partitioning of acyl‐CoAs. Biochemistry 38(48): 15840–15847.
Aoyama T, Peters JM, Iritani N, et al. (1998) Altered constitutive expression of fatty acid‐metabolizing enzymes in mice lacking the peroxisome proliferator‐activated receptor alpha (PPARalpha). Journal of Biological Chemistry 273(10): 5678–5684.
Binas B, Danneberg H, McWhir J, Mullins L and Clark AJ (1999) Requirement for the heart‐type fatty acid binding protein in cardiac fatty acid utilization. FASEB Journal 13(8): 805–812.
Black PN, Faergeman NJ and DiRusso CC (2000) Long‐chain acyl‐CoA‐dependent regulation of gene expression in bacteria, yeast and mammals. Journal of Nutrition 130(2S Supplement): 305S–309S.
Bonnefont JP, Demaugre F, Prip‐Buus C, et al. (1999) Carnitine palmitoyltransferase deficiencies. Molecular Genetics and Metabolism 68(4): 424–440.
Broadway NM and Saggerson ED (1995) Solubilization and separation of two distinct carnitine acyltransferases from hepatic microsomes: characterization of the malonyl–CoA‐sensitive enzyme. Biochemical Journal 310(3): 989–995.
Carey GB (1998) Mechanisms regulating adipocyte lipolysis. Advances in Experimental Medicine and Biology 441: 157–170.
Cook GA and Park EA (1999) Expression and regulation of carnitine palmitoyltransferase‐Iα and ‐Iβ genes. American Journal of the Medical Sciences 318(1): 43–48.
Eaton S, Middleton B and Bartlett K (1998) Control of mitochondrial β‐oxidation: sensitivity of the trifunctional protein to [NAD+]/[NADH] and [acetyl‐CoA]/[CoA]. Biochimica et Biophysica Acta 1429(1): 230–238.
Egan JJ, Greenberg AS, Chang MK et al. (1992) Mechanism of hormone‐stimulated lipolysis in adipocytes: translocation of hormone‐sensitive lipase to the lipid storage droplet. Proceedings of the National Academy of Sciences of the USA 89(18): 8537–8541.
Frohnert BI and Bernlohr DA (2000) Regulation of fatty acid transporters in mammalian cells. Progress in Lipid Research 39(1): 83–107.
Gordon DA and Jamil H (2000) Progress towards understanding the role of microsomal triglyceride transfer protein in apolipoprotein‐B lipoprotein assembly. Biochimica et Biophysica Acta 1486(1): 72–83.
Hamilton JA (1998) Fatty acid transport: difficult or easy? Journal of Lipid Research 39(3): 467–481.
Kaikaus RM, Chan WK, Lysenko N et al. (1993) Induction of peroxisomal fatty acid β‐oxidation and liver fatty acid‐binding protein by peroxisome proliferators. Mediation via the cytochrome P‐450IVA1 omega‐hydroxylase pathway. Journal of Biological Chemistry 268(13): 9593–9603.
Keller U, Lustenberger M, Muller‐Brand J, Gerber PP and Stauffacher W (1989) Human ketone body production and utilization studied using tracer techniques: regulation by free fatty acids, insulin, catecholamines, and thyroid hormones. Diabetes/Metabolism Reviews 5(3): 285–298.
Knudsen J, Neergaard TB, Gaigg B, Jensen MV and Hansen JK (2000) Role of acyl‐CoA binding protein in acyl‐CoA metabolism and acyl‐CoA‐mediated cell signaling. Journal of Nutrition 130(2S Supplement): 294S–298S.
Large V, Arner P, Reynisdottir S et al. (1998) Hormone‐sensitive lipase expression and activity in relation to lipolysis in human fat cells. Journal of Lipid Research 39(8): 1688–1695.
Lazarow PB and De Duve C (1976) A fatty acyl‐CoA oxidizing system in rat liver peroxisomes; enhancement by clofibrate, a hypolipidemic drug. Proceedings of the National Academy of Sciences of the USA 73(6): 2043–2046.
Memon RA, Fuller J, Moser AH et al. (1999) Regulation of putative fatty acid transporters and acyl‐CoA synthetase in liver and adipose tissue in ob/ob mice. Diabetes 48(1): 121–127.
Park EA and Cook GA (1998) Differential regulation in the heart of mitochondrial carnitine palmitoyltransferase‐I muscle and liver isoforms. Molecular and Cellular Biochemistry 180(1–2): 27–32.
van Veldhoven PP and Mannaerts GP (1999) Role and organization of peroxisomal beta‐oxidation. Advances in Experimental Medicine and Biology 466: 261–272.
Wolfe RR and Peters EJ (1987) Lipolytic response to glucose infusion in human subjects. American Journal of Physiology 252(2 Pt 1): E218–E223.
Wolfe RR (1998) Metabolic interactions between glucose and fatty acids in humans. American Journal of Clinical Nutrition 67(3 Supplement): 519S–526S.
Zammit VA (1999) Carnitine acyltransferases: functional significance of subcellular distribution and membrane topology. Progress in Lipid Research 38(3): 199–224.
Further Reading
Bonen A, Luiken JJ and Glatz JF (2002) Regulation of fatty acid transport and membrane transporters in health and disease. Molecular and Cellular Biochemistry 239: 181–192.
Bremer J (2001) The biochemistry of hypo‐ and hyperlipidemic fatty acid derivatives: metabolism and metabolic effects. Progress in Lipid Research 40: 231–268.
Drynan L, Quant PA and Zammit VA (1996) Flux control exerted by mitochondrial outer membrane carnitine palmitoyltransferase over beta‐oxidation, ketogenesis and tricarboxylic acid cycle activity in hepatocytes isolated from rats in different metabolic states. Biochemical Journal 317(3): 791–795.
Luiken JJFP, Schaap FG, van Nieuwenhoven FA, et al. (1999) Cellular fatty acid transport in heart and skeletal muscle as facilitated by proteins. Lipids 34(Suppl): S169–S175.
Mannaerts GP and van Veldhoven PP (1993) Metabolic pathways in mammalian peroxisomes. Biochimie 75(3–4): 147–158.
Quant PA and Eaton S (eds) (1998) Current Views of Fatty Acid Oxidation and Ketogenesis from Organelles to Point Mutations. Advances in Experimental and Medicine and Biology, vol. 466. New York: Kluwer Academic/Plenum Publishers.
Rasmussen BB and Wolfe RR (1999) Regulation of fatty acid oxidation in skeletal muscle. Annual Review of Nutrition 9: 463–484.
Shrago E (2000) Long‐chain acyl‐CoA as a multi‐effector ligand in cellular metabolism. Journal of Nutrition 130(2S Supplement): 290S–293S.
van Veldhoven PP and Mannaerts GP (1999) Role and organization of peroxisomal beta‐oxidation. In: Quant PA and Eaton S (eds) Advances in Experimental Biology and Medicine, vol. 466, pp. 261–272. New York: Kluwer Academic/Plenum Publishers
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