Abstract
Peroxisomes play a key role in human physiology as exemplified by the devastating consequences of a defect in peroxisome biogenesis as observed in patients affected by Zellweger syndrome. The main metabolic functions of peroxisomes in humans include: (1) fatty acid beta-oxidation; (2) etherphospholipid synthesis; (3) bile acid synthesis; (4) fatty acid alpha-oxidation, and (5) glyoxylate detoxification. Since peroxisomes lack a citric acid cycle and respiratory chain like mitochondria do, metabolism in peroxisomes requires continued cross-talk with other organelles, notably mitochondria and the endoplasmic reticulum in order to allow continued metabolism of the products generated by peroxisomes. Many of the metabolites which require peroxisomes for homeostasis, are involved in signal transduction pathways. These include the primary bile acids; platelet activating factor; plasmalogens, N-acylglycines and N-acyltaurines; docosahexaenoic acid as well as multiple prostanoids. The current state of knowledge in this area will be discussed in this review.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Abbreviations
- Acnat:
-
Acyl-CoA: amino acid N-acyltransferase
- ACOX1:
-
Acyl-CoA oxidase 1
- ACYL-DHAP:
-
Acyldihydroxyacetone phosphate
- ADHAPS:
-
Alkyldihydroxyacetone phosphate synthase
- AGT:
-
Alanine glyoxylate aminotransferase
- ALD:
-
Adrenoleukodystrophy
- BAAT:
-
Bile acid-CoA: amino acid N-acetyltransferase
- BCOX:
-
Branched-chain acyl-CoA oxidase
- BSEP:
-
Bile salt export pump
- CA:
-
Cholic acid
- CDCA:
-
Chenodeoxycholic acid
- CPT1:
-
Carnitine palmityltransferase 1
- CrAT:
-
Carnitine acetyltransferase
- CrOT:
-
Carnitine octanoyltransferase
- CYP7A1:
-
Cholesterol 7-Alpha-hydroxylase
- DBP:
-
D-bifunctional protein
- DHA:
-
Docosahexaenoic acid
- DHCA:
-
Dihydroxycholestanoic acid
- DHAPAT:
-
Dihydroxyacetone phosphate acyltransferase
- EPL:
-
Etherphospholipid
- ER:
-
Endoplasmic reticulum
- FA:
-
Fatty acid
- FGF:
-
Fibroblasts growth factor
- FXR:
-
Farnesoid-X receptor
- LBP:
-
L-bifunctional protein
- LRH-1:
-
Liver receptor homologous Protein-1
- LRM:
-
Lipid raft microdomains
- LTE4:
-
Cysteinyl leukotriene-4
- PAF:
-
Platelet activating factor
- PD:
-
Peroxisomal disorder
- ROS:
-
reactive oxygen species
- SCPx:
-
Sterol-carrier-protein X
- TH:
-
Thiolase
- THCA:
-
Trihydroxycholestanoic acid
- VLCFA:
-
Very long-chain fatty acids
- ZS:
-
Zellweger syndrome
References
Baumgart E, Fahimi HD, Stich A, Volkl A (1996) L-lactate dehydrogenase A4- and A3B isoforms are bona fide peroxisomal enzymes in rat liver. Evidence for involvement in intraperoxisomal NADH reoxidation. J Biol Chem 271:3846–3855
Beenken A, Mohammadi M (2009) The FGF family: biology, pathophysiology and therapy. Nat Rev Drug Discov 8:235–253
Bradshaw HB, Walker JM (2005) The expanding field of cannabimimetic and related lipid mediators. Br J Pharmacol 144:459–465
Brites P, Waterham HR, Wanders RJA (2004) Functions and biosynthesis of plasmalogens in health and disease. Biochim Biophys Acta 1636:219–231
Brown FR, McAdams AJ, Cummins JW, Konkol R, Singh I, Moser AB, Moser HW (1982) Cerebro-hepato-renal (Zellweger) syndrome and neonatal adrenoleukodystrophy: similarities in phenotype and accumulation of very long chain fatty acids. Johns Hopkins Med J 151:344–351
Cartier N, Hacein-Bey-Abina S, Bartholomae CC, Veres G, Schmidt M, Kutschera I, Vidaud M, Abel U, Dal-Cortivo L, Caccavelli L, Mahlaoui N, Kiermer V, Mittelstaedt D, Bellesme C, Lahlou N, Lefrere F, Blanche S, Audit M, Payen E, Leboulch P, l’Homme B, Bougneres P, Von KC, Fischer A, Cavazzana-Calvo M, Aubourg P (2009) Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science 326:818–823
Cooper TG, Beevers H (1969) Beta oxidation in glyoxysomes from castor bean endosperm. J Biol Chem 244:3514–3520
de Waart DR, Koomen GC, Wanders RJA (1994) Studies on the urinary excretion of thromboxane B2 in Zellweger patients and control subjects: evidence for a major role for peroxisomes in the beta-oxidative chain-shortening of thromboxane B2. Biochim Biophys Acta 1226:44–48
del RÃo LA (2011) Peroxisomes as a cellular source of reactive nitrogen species signal molecules. Arch Biochem Biophys 506:1–11
del RÃo LA, Corpas FJ, Sandalio LM, Palma JM, Gomez M, Barroso JB (2002) Reactive oxygen species, antioxidant systems and nitric oxide in peroxisomes. J Exp Bot 53:1255–1272
del RÃo LA, Sandalio LM, Corpas FJ, Palma JM, Barroso JB (2006) Reactive oxygen species and reactive nitrogen species in peroxisomes. Production, scavenging, and role in cell signaling. Plant Physiol 141:330–335
Diczfalusy U, Kase BF, Alexson SE, Bjorkhem I (1991) Metabolism of prostaglandin F2 alpha in Zellweger syndrome. Peroxisomal beta-oxidation is a major importance for in vivo degradation of prostaglandins in humans. J Clin Invest 88:978–984
Diczfalusy U, Vesterqvist O, Kase BF, Lund E, Alexson SE (1993) Peroxisomal chain-shortening of thromboxane B2: evidence for impaired degradation of thromboxane B2 in Zellweger syndrome. J Lipid Res 34:1107–1113
Ebberink MS, Koster J, Visser G, van Spronsen FJ, Stolte-Dijkstra I, Smit GPA, Fock JM, Kemp S, Wanders RJA, Waterham HR (2012) A novel human defect of peroxisome division due to a homozygous non-sense mutation in the PEX11 beta gene. J Med Genet 49:307–313
Fransen M, Nordgren M, Wang B, Apanasets O (2012) Role of peroxisomes in ROS/RNS-metabolism: Implications for human disease. Biochim Biophys Acta 1822:1363–1373
Goldfischer S, Moore CL, Johnson AB, Spiro AJ, Valsamis MP, Wisniewski HK, Ritch RH, Norton WT, Rapin I, Gartner LM (1973) Peroxisomal and mitochondrial defects in the cerebro-hepato- renal syndrome. Science 182:62–64
Gorgas K, Teigler A, Komljenovic D, Just WW (2006) The ether lipid-deficient mouse: tracking down plasmalogen functions. Biochim Biophys Acta 1763:1511–1526
Hertz R, Magenheim J, Berman I, Bar-Tana J (1998) Fatty acyl-CoA thioesters are ligands of hepatic nuclear factor-4alpha. Nature 392:512–516
Heymans HSA, Schutgens RBH, Tan R, van den Bosch H, Borst P (1983) Severe plasmalogen deficiency in tissues of infants without peroxisomes (Zellweger syndrome). Nature 306:69–70
Holt JA, Luo G, Billin AN, Bisi J, McNeill YY, Kozarsky KF, Donahee M, Wang DY, Mansfield TA, Kliewer SA, Goodwin B, Jones SA (2003) Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis. Genes Dev 17:1581–1591
Houten SM, Denis S, Argmann CA, Jia Y, Ferdinandusse S, Reddy JK, Wanders RJA (2012) Peroxisomal L-bifunctional enzyme (Ehhadh) is essential for the production of medium-chain dicarboxylic acids. J Lipid Res 53:1296–1303
Hunt MC, Siponen MI, Alexson SE (2012) The emerging role of acyl-CoA thioesterases and acyltransferases in regulating peroxisomal lipid metabolism. Biochim Biophys Acta 1822:1397–1410
Inagaki T, Choi M, Moschetta A, Peng L, Cummins CL, McDonald JG, Luo G, Jones SA, Goodwin B, Richardson JA, Gerard RD, Repa JJ, Mangelsdorf DJ, Kliewer SA (2005) Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab 2:217–225
Jedlitschky G, Mayatepek E, Keppler D (1993) Peroxisomal leukotriene degradation: biochemical and clinical implications. Adv Enzyme Regul 33:181–194
Jump DB, Botolin D, Wang Y, Xu J, Christian B, Demeure O (2005) Fatty acid regulation of hepatic gene transcription. J Nutr 135:2503–2506
Kliewer SA, Sundseth SS, Jones SA, Brown PJ, Wisely GB, Koble CS, Devchand P, Wahli W, Willson TM, Lenhard JM, Lehmann JM (1997) Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proc Natl Acad Sci USA 94:4318–4323
Kohno M, Hasegawa H, Inoue A, Muraoka M, Miyazaki T, Oka K, Yasukawa M (2006) Identification of N-arachidonylglycine as the endogenous ligand for orphan G-protein-coupled receptor GPR18. Biochem Biophys Res Commun 347:827–832
Kruska N, Reiser G (2011) Phytanic acid and pristanic acid, branched-chain fatty acids associated with Refsum disease and other inherited peroxisomal disorders, mediate intracellular Ca2+ signaling through activation of free fatty acid receptor GPR40. Neurobiol Dis 43:465–472
Kurosu H, Choi M, Ogawa Y, Dickson AS, Goetz R, Eliseenkova AV, Mohammadi M, Rosenblatt KP, Kliewer SA, Kuro-o M (2007) Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. J Biol Chem 282:26687–26695
Lazarow PB, De Duve C (1976) A fatty acyl-CoA oxidizing system in rat liver peroxisomes; enhancement by clofibrate, a hypolipidemic drug. Proc Natl Acad Sci USA 73:2043–2046
Lu J, Caplan MS, Li D, Jilling T (2008) Polyunsaturated fatty acids block platelet-activating factor-induced phosphatidylinositol 3 kinase/Akt-mediated apoptosis in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 294:G1181–G1190
Mayatepek E, Flock B (1999) Increased urinary excretion of LTB4 and omega-carboxy-LTB4 in patients with Zellweger syndrome. Clin Chim Acta 282:151–155
Mayatepek E, Ferdinandusse S, Meissner T, Wanders RJA (2004) Analysis of cysteinyl leukotrienes and their metabolites in bile of patients with peroxisomal or mitochondrial beta-oxidation defects. Clin Chim Acta 345:89–92
O’Byrne J, Hunt MC, Rai DK, Saeki M, Alexson SE (2003) The human bile acid-CoA:amino acid N-acyltransferase functions in the conjugation of fatty acids to glycine. J Biol Chem 278:34237–34244
Oh DY, Yoon JM, Moon MJ, Hwang JI, Choe H, Lee JY, Kim JI, Kim S, Rhim H, O’Dell DK, Walker JM, Na HS, Lee MG, Kwon HB, Kim K, Seong JY (2008) Identification of farnesyl pyrophosphate and N-arachidonylglycine as endogenous ligands for GPR92. J Biol Chem 283:21054–21064
Pellicoro A, van den Heuvel FA, Geuken M, Moshage H, Jansen PL, Faber KN (2007) Human and rat bile acid-CoA:amino acid N-acyltransferase are liver-specific peroxisomal enzymes: implications for intracellular bile salt transport. Hepatology 45:340–348
Perichon R, Moser AB, Wallace WC, Cunningham SC, Roth GS, Moser HW (1998) Peroxisomal disease cell lines with cellular plasmalogen deficiency have impaired muscarinic cholinergic signal transduction activity and amyloid precursor protein secretion. Biochem Biophys Res Commun 248:57–61
Reilly SJ, O’Shea EM, Andersson U, O’Byrne J, Alexson SE, Hunt MC (2007) A peroxisomal acyltransferase in mouse identifies a novel pathway for taurine conjugation of fatty acids. FASEB J 21:99–107
Reiser G, Schonfeld P, Kahlert S (2006) Mechanism of toxicity of the branched-chain fatty acid phytanic acid, a marker of Refsum disease, in astrocytes involves mitochondrial impairment. Int J Dev Neurosci 24:113–122
Rodemer C, Thai TP, Brugger B, Kaercher T, Werner H, Nave KA, Wieland F, Gorgas K, Just WW (2003) Inactivation of ether lipid biosynthesis causes male infertility, defects in eye development and optic nerve hypoplasia in mice. Hum Mol Genet 12:1881–1895
Ronicke S, Kruska N, Kahlert S, Reiser G (2009) The influence of the branched-chain fatty acids pristanic acid and Refsum disease-associated phytanic acid on mitochondrial functions and calcium regulation of hippocampal neurons, astrocytes, and oligodendrocytes. Neurobiol Dis 36:401–410
Roy M-O, Hannedouche S (2007) Ligand for G-protein coupled receptor GPR72 and uses thereof, Canadian Patent Application, pp 1–99
Saghatelian A, McKinney MK, Bandell M, Patapoutian A, Cravatt BF (2006) A FAAH-regulated class of N-acyl taurines that activates TRP ion channels. Biochemistry 45:9007–9015
Salido E, Pey AL, Rodriguez R, Lorenzo V (2012) Primary hyperoxalurias: disorders of glyoxylate detoxification. Biochim Biophys Acta 1822:1453–1464
Savary S, Trompier D, Andreoletti P, Le BF, Demarquoy J, Lizard G (2012) Fatty acids – induced lipotoxicity and inflammation. Curr Drug Metab 13:1358–1370
Spector AA, Fang X, Snyder GD, Weintraub NL (2004) Epoxyeicosatrienoic acids (EETs): metabolism and biochemical function. Prog Lipid Res 43:55–90
Stables MJ, Gilroy DW (2011) Old and new generation lipid mediators in acute inflammation and resolution. Prog Lipid Res 50:35–51
Stroeve JH, Brufau G, Stellaard F, Gonzalez FJ, Staels B, Kuipers F (2010) Intestinal FXR-mediated FGF15 production contributes to diurnal control of hepatic bile acid synthesis in mice. Lab Invest 90:1457–1467
Tan B, O’Dell DK, Yu YW, Monn MF, Hughes HV, Burstein S, Walker JM (2010) Identification of endogenous acyl amino acids based on a targeted lipidomics approach. J Lipid Res 51:112–119
Tsikas D, Schwedhelm E, Fauler J, Gutzki FM, Mayatepek E, Frolich JC (1998) Specific and rapid quantification of 8-iso-prostaglandin F2alpha in urine of healthy humans and patients with Zellweger syndrome by gas chromatography-tandem mass spectrometry. J Chromatogr B Biomed Sci Appl 716:7–17
van Roermund CWT, Elgersma Y, Singh N, Wanders RJA, Tabak HF (1995) The membrane of peroxisomes in Saccharomyces cerevisiae is impermeable to NAD(H) and acetyl-CoA under in vivo conditions. EMBO J 14:3480–3486
van Roermund CWT, Hettema EH, Kal AJ, van den Berg M, Tabak HF, Wanders RJA (1998) Peroxisomal beta-oxidation of polyunsaturated fatty acids in Saccharomyces cerevisiae: isocitrate dehydrogenase provides NADPH for reduction of double bonds at even positions. EMBO J 17:677–687
Van Veldhoven PP (2010) Biochemistry and genetics of inherited disorders of peroxisomal fatty acid metabolism. J Lipid Res 51:2863–2895
Vanhove GF, Van Veldhoven PP, Fransen M, Denis S, Eyssen HJ, Wanders RJA, Mannaerts GP (1993) The CoA esters of 2-methyl-branched chain fatty acids and of the bile acid intermediates di- and trihydroxycoprostanic acids are oxidized by one single peroxisomal branched chain acyl-CoA oxidase in human liver and kidney. J Biol Chem 268:10335–10344
Verhoeven NM, Roe DS, Kok RM, Wanders RJA, Jakobs C, Roe C (1998) Phytanic acid and pristanic acid are oxidized by sequential peroxisomal and mitochondrial reactions in cultured fibroblasts. J Lipid Res 39:66–74
Wanders RJA, Brites P (2010) Biosynthesis of ether-phospholipids including plasmalogens, peroxisomes and human disease: new insights into an old problem. Clin Lipidol 5:379–386
Wanders RJA, Waterham HR (2006) Biochemistry of mammalian peroxisomes revisited. Annu Rev Biochem 75:295–332
Wanders RJA, Komen JC, Ferdinandusse S (2011) Phytanic acid metabolism in health and disease. Biochim Biophys Acta 1811:498–507
Waterham HR, Koster J, van Roermund CWT, Mooyer PAW, Wanders RJA, Leonard JV (2007) A lethal defect of mitochondrial and peroxisomal fission. N Engl J Med 356:1736–1741
Yoshikawa T, Shimano H, Yahagi N, Ide T, Amemiya-Kudo M, Matsuzaka T, Nakakuki M, Tomita S, Okazaki H, Tamura Y, Iizuka Y, Ohashi K, Takahashi A, Sone H, Osuga JJ, Gotoda T, Ishibashi S, Yamada N (2002) Polyunsaturated fatty acids suppress sterol regulatory element-binding protein 1c promoter activity by inhibition of liver X receptor (LXR) binding to LXR response elements. J Biol Chem 277:1705–1711
Acknowledgement
The author gratefully acknowledges Mrs. Maddy Festen for expert preparation of the manuscript and Mr. Jos Ruiter for artwork.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2013 Springer Science+Business Media Dordrecht
About this chapter
Cite this chapter
Wanders, R.J.A. (2013). Peroxisomes in Human Health and Disease: Metabolic Pathways, Metabolite Transport, Interplay with Other Organelles and Signal Transduction. In: del RÃo, L. (eds) Peroxisomes and their Key Role in Cellular Signaling and Metabolism. Subcellular Biochemistry, vol 69. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-6889-5_2
Download citation
DOI: https://doi.org/10.1007/978-94-007-6889-5_2
Published:
Publisher Name: Springer, Dordrecht
Print ISBN: 978-94-007-6888-8
Online ISBN: 978-94-007-6889-5
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)