Author's personal copy Review Peroxisomes, lipid metabolism and lipotoxicity R.J.A. Wanders a,b, ⁎, S. Ferdinandusse a,b , P. Brites c , S. Kemp a,b a University of Amsterdam, Academic Medical Center, Department of Clinical Chemistry, Laboratory of Genetic Metabolic Diseases, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands b University of Amsterdam, Academic Medical Center, Department of Pediatrics, Emma Children's Hospital, Laboratory of Genetic Metabolic Diseases, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands c IBMC Lab Nerve Regeneration, Rua do Campo Alegre 8234150-180 Porto, Portugal abstract article info Article history: Received 13 November 2009 Received in revised form 7 January 2010 Accepted 7 January 2010 Available online 12 January 2009 Keywords: Fatty acid oxidation Fatty acid Plasmalogen Bile acid Zellweger syndrome Adrenoleukodystrophy Refsum disease Peroxisomes play an essential role in cellular lipid metabolism as exemplified by the existence of a number of genetic diseases in humans caused by the impaired function of one of the peroxisomal enzymes involved in lipid metabolism. Key pathways in which peroxisomes are involved include: (1.) fatty acid beta-oxidation; (2.) etherphospholipid biosynthesis, and (3.) fatty acid alpha-oxidation. In this paper we will describe these different pathways in some detail and will provide an overview of peroxisomal disorders of metabolism and in addition discuss the toxicity of the intermediates of peroxisomal metabolism as they accumulate in the different peroxisomal deficiencies. © 2010 Elsevier B.V. All rights reserved. 1. Introduction Although originally underrated as organelles of relatively little physiological significance, peroxisomes are now known to play a crucial role in human physiology. The best evidence in support of this conclusion comes from the fact that a genetically determined inability to synthesize peroxisomes gives rise to severe clinical abnormalities with multiple aberrations and early death. Indeed, patients suffering from the cerebro-hepato-renal syndrome of Zellweger (in short: Zellweger syndrome), show a wide range of abnormalities, including neurological, craniofacial, ocular, hepatological and other aberrations. Zellweger patients lack peroxisomes in all body cells leading to a generalized loss of peroxisomal functions. The first evidence that peroxisomes are involved in lipid metabolism came in the early 1980s when two key observations were published. The first paper documented the accumulation of very-long-chain fatty acids (VLCFA) in plasma from Zellweger patients [1], whereas in the second publication the complete deficiency of plasmalogens in tissues of Zellweger patients was described [2]. Soon after these seminal papers by Brown et al. [1] and Heijmans et al. [2], Poulos et al. [3] reported the accumulation of phytanic acid in plasma from Zellweger patients. Phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) is a branched-chain fatty acid, which because of the presence of a methyl-group at the 3- position cannot be beta-oxidized and instead undergoes one cycle of alpha-oxidation. The finding that phytanic acid accumulates in Zellweger patients [3], was the first indication pointing to a key role of peroxisomes in fatty acid (FA) alpha-oxidation. In this paper, we will 1) describe the peroxisomal lipid pathways in some detail, 2) give an overview of peroxisomal disorders of lipid metabolism and 3) focus on the toxicity of the intermediates of peroxisomal lipid metabolism as they accumulate in the different peroxisomal deficiencies. 1.1. Peroxisomal fatty acid beta-oxidation At present, three different types of fatty acids are known to rely fully on peroxisomes for beta-oxidation. These include: (1.) VLCFA like C24:0, and C26:0; (2.) the 2-methyl branched-chain fatty acid pristanic acid (2,6,10,14-tetramethylpentadecanoic acid), and (3.) the bile acid synthesis intermediates dihydroxycholestanoic acid (DHCA) and trihydroxycholestanoic acid (THCA). In addition to these exclusive peroxisomal substrates, there are other fatty acids, which can be beta-oxidized in both mitochondria and peroxisomes, whereas some fatty acids can only be oxidized in mitochondria, including short-chain fatty acids and 4,8-dimethylnonanoic acid, an intermedi- ate in pristanic acid beta-oxidation [4]. Peroxisomes contain the full enzymatic machinery to beta-oxidize fatty acids, although oxidation does not go to completion. This has Biochimica et Biophysica Acta 1801 (2010) 272–280 ⁎ Corresponding author. Laboratory Genetic Metabolic Diseases, Room F0-226, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Tel.: + 31 20 5665958/5664197; fax: + 31 20 6962596. E-mail address: r.j.wanders@amc.uva.nl (R.J.A. Wanders). 1388-1981/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.bbalip.2010.01.001 Contents lists available at ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbalip