MINIREVIEW Fatty acid omega-oxidation as a rescue pathway for fatty acid oxidation disorders in humans Ronald J A Wanders, Jasper Komen and Stephan Kemp Academic Medical Center, University of Amsterdam, The Netherlands Keywords adrenoleukodystrophy; cytochrome P450; fatty acids; mitochondria; peroxisomes; Refsum disease; Zellweger syndrome; a-oxidation; b-oxidation; x-oxidation Correspondence R J A Wanders, Genetic Metabolic Diseases, Room F0-226, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands Fax: +31 (0)20 6962596 Tel: +31 (0)20 5665958 ⁄ 5664197 E-mail: r.j.wanders@amc.uva.nl Fatty acids (FAs) can be degraded via different mechanisms including a-, b- and x-oxidation In humans, a range of different genetic diseases has been identified in which either mitochondrial FA b-oxidation, peroxisomal FA b-oxidation or FA a-oxidation is impaired Treatment options for most of these disorders are limited This has prompted us to study FA x-oxidation as a rescue pathway for these disorders, based on the notion that if the x-oxidation of specific FAs could be upregulated one could reduce the accumulation of these FAs and the subsequent detrimental effects in the different groups of disorders In this minireview, we describe our current state of knowledge in this area with special emphasis on Refsum disease and X-linked adrenoleukodystrophy (Received 22 June 2010, revised 28 September 2010, accepted November 2010) doi:10.1111/j.1742-4658.2010.07947.x Introduction In general, fatty acids (FAs) can be degraded via different mechanisms, including a-, b- and x-oxidation (Fig 1) In humans a-oxidation takes place in peroxisomes only, whereas both peroxisomes and mitochondria are able to b-oxidize FAs Importantly, in recent years a great number of genetically determined disorders in humans has been described in which either FA a-oxidation or FA b-oxidation in mitochondria or peroxisomes is deficient As discussed in more detail below, treatment options for each of the different groups of FA oxidation disorders is limited, which prompted us to investigate x-oxidation as a rescue pathway for these disorders This is based on the notion that if it was possible to upregulate the x-oxidation of specific FAs known to accumulate in the different disorders, one could reduce the accumulation of these FAs under in vivo conditions and thereby counteract the detrimental effects associated with the accumulation of these FAs and their derivatives, which are the basis of the clinical signs and symptoms observed in the different (groups of) disorders We first briefly describe FA a- and b-oxidation pathways and the disorders involved and then describe the current state of knowledge regarding x-oxidation as a rescue pathway for Refsum disease and X-linked adrenoleukodystrophy (X-ALD) Abbreviations ATRA, all-trans-retinoic acid; CCALD, childhood cerebral adrenoleukodystrophy; FA, fatty acid; LTB4, leukotriene B4; PPAR, peroxisome proliferator-activated receptor; VLCFA, very long-chain fatty acid; X-ALD, X-linked adrenoleukodystrophy 182 FEBS Journal 278 (2011) 182–194 ª 2010 The Authors Journal compilation ª 2010 FEBS R J A Wanders et al Fatty acid oxidation disorders Fig Schematic diagram depicting the different mechanisms by which fatty acids can be oxidized (see text) General aspects of fatty acid oxidation Beta-oxidation is the preferred way of oxidizing FAs In principle, each FA can be b-oxidized, including straight- and branched-chain FAs, as well as monoand polyunsaturated FAs There is one exception, however, and that is if the carbon-3 has a methyl- or any other functional group attached In such cases, degradation can only occur by a- or x-oxidation Until a few years ago, the enzymology of the a-oxidation system remained unresolved and its subcellular localization heavily disputed This has now changed; the basic chemistry of the pathway has been delineated and the enzymes involved in a-oxidation and their subcellular localization have been identified and characterized, although some questions remain [1,2] Mitochondrial fatty acid b-oxidation and its disorders Mitochondria catalyze the b-oxidation of the majority of FAs and contain the full enzymatic machinery to oxidize straight-chain, 2-methyl-branched-chain, and mono- and polyunsaturated FAs After uptake of FAs into the cells via a mechanism which remains incompletely understood, but probably involves CD36 [3], FAs are rapidly converted into coenzyme A (CoA)esters by one of the many acyl-CoA synthetases either of the long-chain or very long-chain acyl-CoA synthetase family [4] Subsequently, the acyl-CoA esters are transferred across the mitochondrial membrane by means of the carnitine cycle, which involves carnitine palmitoyltransferase I, mitochondrial carnitine acylcarnitine translocase and carnitine palmitoyltransferase II [5–7] In case of the straight-chain and 2-methyl-branched chain FAs, b-oxidation can start right away via the well-established cascade of four steps involving dehydrogenation, hydratation, dehydrogenation again and thiolytic cleavage of the acyl-CoA esters Each step of the b-oxidation spiral is not catalyzed by one single enzyme but by multiple chain-length-specific enzymes For example, at least three different acyl-CoA dehydrogenases are involved in the oxidation of saturated long-chain FAs These include very long-chain acylCoA dehydrogenase, medium-chain acyl-CoA dehydrogenase and short-chain acyl-CoA dehydrogenase The same is true for the third step in mitochondrial fatty acid b-oxidation, with at least two different enzymes involved including short-chain 3-hydroxyacylCoA dehydrogenase and long-chain 3-hydroxyacylCoA dehydrogenase The latter enzyme is part of a larger enzyme complex called mitochondrial trifunctional protein with additional enoyl-CoA hydratase and 3-ketothiolase activities Defects in each of these enzymes have been identified (see Table 1) Although the clinical signs and symptoms of patients vary depending on the type of enzyme defect and the extent of the deficiency, a general characteristic of all disorders of mitochondrial FA oxidation is hypoketotic hypoglycemia which may be life threatening, and cardiomyopathy, especially in the case of the long-chain fatty oxidation defects such as mitochondrial carnitine acylcarnitine translocase deficiency, carnitine palmitoyltransferase II deficiency, very long-chain acyl-CoA dehydrogenase deficiency and long-chain 3-hydroxyacyl-CoA dehydrogenase ⁄ mitochondrial trifunctional protein deficiency [8,9] With the exception of dietary measures consisting of a diet rich in carbohydrates and low in fat taken at frequent intervals, there are virtually no realistic treatment options FEBS Journal 278 (2011) 182–194 ª 2010 The Authors Journal compilation ª 2010 FEBS 183 Fatty acid oxidation disorders R J A Wanders et al Table The mitochondrial and peroxisomal beta-oxidation deficiencies Mitochondrial fatty acid oxidation disorders Mutant gene Deficient enzyme Locus OMIM Carnitine palmitoyl-CoA transferase-1 deficiency Carnitine ⁄ acylcarnitine translocase deficiency Carnitine palmitoyl-CoA transferase-2 deficiency Very long-chain acyl-CoA dehydrogenase deficiency Medium-chain acyl-CoA dehydrogenase deficiency Short-chain acyl-CoA dehydrogenase deficiency Isolated long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency Isolated long-chain 3-ketothiolase deficiency Complete mitochondrial trifunctional protein deficiency Short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency Medium-chain 3-ketoacyl-CoA thiolase deficiency ETF dehydrogenase deficiency ETF-alpha deficiency ETF-beta deficiency 2,4-dienoyl-CoA reductase deficiency CPT1A SLC25A2 CPT2 ACADVL ACADM ACADS HADHA HADHB HADHA HADHB HADHSC ACAA2 ETFDH ETFA ETFB DECR1 CPT1A CACT CPT2 VLCAD MCAD SCAD LCHAD LCKAT LCHAD LCKAT SCHAD MCKAT ETFDH ETFa ETFb DECR1 11q13 3p21 1p32 17p11 1p31 12q22 2p23 2p23 2p23 2p23 4q22 4q32 15q23 19q13 8q21 600528 ⁄ 255120 212138 600649 ⁄ 255110 201475 201450 201470 600890 143450 600890 143450 601609 602199 231675 608053 130410 222745 Peroxiomal fatty acid oxidation disorders X-linked adrenoleukodystrophy Acyl-CoA oxidase deficiency D-Bifunctional protein deficiency 2-methylacyl-CoA racemase deficiency Peroxisomal sterol carrier protein x (SCPx) deficiency ABCD1 ACOX1 HSD17B4 AMACR SCP2 ALDP ACOX1 DBP ⁄ MFP2 AMACR SCPx Xq28 17q25.1 5q2 5p13.3-p12 1p32 300100 264470 261515 604489 – Peroxisomal a-oxidation and its disorders FA a-oxidation allows the chain-shortening of FAs by one carbon atom and takes place in peroxisomes only A typical 3-methyl-branched-chain FA like phytanic acid (3,7,11,15-tetramethylhexadecanoic acid), is completely dependent on a normal functioning a-oxidation system in order to be oxidized A defect in the a-oxidation system is reflected in the accumulation of phytanic acid in the tissues and body fluids of patients [1,2,10] Alpha-oxidation of phytanic acids starts with the formation of the CoA-ester, i.e phytanoyl-CoA, followed by hydroxylation to generate 2-hydroxyphytanoyl-CoA, a reaction catalyzed by the enzyme phytanoyl-CoA 2-hydroxylase Subsequently, 2-hydroxyphytanoyl-CoA is cleaved by the enzyme 2-hydroxyacyl-CoA lyase to pristanal and formyl-CoA, which is then hydrolyzed to formic acid and coenzyme A (CoASH) Pristanal is then oxidized to pristanic acid (2,6,10,14-tetramethylpentadecanoic acid), as catalyzed by a yet undefined peroxisomal aldehyde dehydrogenase After activation to its CoA-ester, pristanoyl-CoA undergoes three cycles of b-oxidation in peroxisomes, after which the end-products are transported to mitochondria for full oxidation [11,12] Alpha-oxidation is deficient in different peroxisomal disorders including the peroxisome biogenesis 184 disorders, in which the primary genetic defect is in one of the many genes involved in peroxisome biogenesis [13–15] To date, however, only one single enzyme deficiency in the a-oxidation pathway per se has been described This is phytanoyl-CoA hydroxylase deficiency with Refsum disease as its disease counterpart [10] Patients suffering from Refsum disease show a late-onset phenotype, dominated by retinitis pigmentosa, culminating in blindness with anosmia, cerebellar ataxia and a range of other more variable abnormalities The only therapy available to date is a life-long diet low in phytanic acid, which may stop further progression of some, but not all, of the symptoms provided the diet is meticulously maintained Peroxisomal fatty acid b-oxidation and its disorders Peroxisomes contain a FA b-oxidation system just like mitochondria, but the individual reactions of the b-oxidation spiral are catalyzed by different enzymes encoded by distinct genes compared with the mitochondrial b-oxidation system [11] Importantly, peroxisomes oxidize a unique set of FAs which cannot be b-oxidized in mitochondria Most important from a clinical point of view are: (a) very long-chain fatty acids (VLCFAs), notably C24:0 and C26:0; (b) pristanic acid (2,6,10,14-tetramethylpentadecanoic acid), as FEBS Journal 278 (2011) 182–194 ª 2010 The Authors Journal compilation ª 2010 FEBS R J A Wanders et al derived directly from dietary sources and indirectly from phytanic acid upon a-oxidation; and (c) di- and trihydroxycholestanoic acid (see [11] for review) Peroxisomes are unable to b-oxidize FAs to completion Instead FAs are only chain-shortened to shorter chain FAs followed by the transfer of these chain-shortened FAs to mitochondria for full oxidation This has been established most firmly for pristanic acid which undergoes three cycles of b-oxidation in peroxisomes to produce propionyl-CoA, acetyl-CoA and 4.8-dimethylnonanoyl-CoA followed by the transfer of these CoA-esters either as carnitine-ester or as free fatty acid to mitochondria for full oxidation to CO2 and H2O [16,17] At present, five different genetically determined single-enzyme deficiencies have been described in humans These include: (a) X-ALD, (b) acyl-CoA oxidase deficiency, (c) D-bifunctional protein deficiency, (d) sterol carrier protein x deficiency and (e) 2-methylacyl-CoA racemase deficiency [18] All five disorders are relatively rare with sterol carrier protein x deficiency described in a single patient only to date [19], 2-methylacyl-CoA racemase-deficiency described in six patients [20] and acyl-CoA oxidase deficiency described in  30 patients [21] Most frequent is X-ALD with an incidence of : 15 000, followed by D-bifunctional protein deficiency [22] X-ALD is a devastating neurological disease which comes in two main phenotypes including childhood cerebral ALD (CCALD) and adrenomyeloneuropathy, together constituting > 80% of all X-ALD patients The most devastating phenotype is CCALD which is characterized by a rapidly progressive cerebral demyelination causing severe disability and death, usually within years after the onset Fatty acid oxidation disorders of symptoms Adrenomyeloneuropathy has a much milder course characterized by a gradually progressive myelopathy and peripheral neuropathy, causing severe disability X-ALD is caused by mutations in the ABCD1 gene which codes for a peroxisomal half-ABC transporter adrenoleukodystrophy protein (ALDP), localized in the peroxisomal membrane as a homodimer ALDP catalyzes the transport of very long-chain FAs across the peroxisomal membrane in the CoA-ester form [23,24] If ALDP is absent or dysfunctional, oxidation of VLCFA is impaired and this leads to the accumulation of VLCFAs in plasma and tissues including the brain of X-ALD patients The VLCFAs that accumulate are not so much derived from the diet, but are synthesized endogenously via chain elongation [24], which explains why a diet low in VLCFAs is of no benefit for X-ALD patients (Fig 2) The only therapeutic options for X-ALD are bone-marrow transplantation and gene therapy, as recently reported by Cartier and Aubourg [25] in three X-ALD boys Fatty acid x-oxidation by CYP450 proteins in humans Early work on FA x-oxidation dates back to the 1930s when Verkade et al [26,27] performed a series of systematic studies that revealed the formation of dicarboxylic acids after administration of medium-chain triglycerides to healthy individuals It was the 1960s before enzymatic studies could be performed using subcellular fractions prepared from guinea-pig, rat and human livers This allowed identification of the pathway intermediates and the subsequent discovery that Fig Schematic diagram illustrating the homeostatic mechanisms involved in C26:0 metabolism Very long-chain fatty acids are predominantly derived from long-chain fatty acids via chain-elongation and degraded via b-oxidation in the peroxisome Several diseases are known in which b-oxidation is deficient including X-linked adrenoleukodystrophy Omega-oxidation of C26:0 involves the participation of different enzymes including CYP4F2 and CYP3FB plus ALDH3A2 The latter converts the x-keto form of C26:0 into the dicarboxylic acid FEBS Journal 278 (2011) 182–194 ª 2010 The Authors Journal compilation ª 2010 FEBS 185 Fatty acid oxidation disorders R J A Wanders et al the enzyme catalyzing the first step of the pathway was in fact a hemoprotein belonging to the ubiquitous discovered family of CYP450s, with members in eukaryotic and prokaryotic species [28–30] The CYP4A subfamily After the successful cloning of CYP4A1 coding for clofibrate-inducible arachidonic acid ⁄ lauric acid x-hydroxylase from rat liver [31], the human homolog of this enzyme was identified and named CYP4A11 [32,33] CYP4A11 turned out to have a broad substrate spectrum and is able to x-hydroxylate the saturated FAs lauric acid, myristic acid (tetradecanoic acid), palmitic acid (hexadecanoic acid) and the unsaturated FAs oleic acid [(Z)-octadec-9-enoic acid] and arachidonic acid (all-cis-5,8,11,14-eicosatetraenoic acid) [34] Recently, another CYP4A subfamily member in humans was identified and designated CYP4A22 [35] This protein is highly homologous with CYP4A11 and not abundantly present in tissues Kawashima et al have expressed the CYP4A22 protein in Escherichia coli, and showed that this protein has lauric acid x-hydroxylase activity [36], but erroneously reported it to be CYP4A11 The CYP4F subfamily CYP4A is not the only subfamily of CYP4 proteins in humans that are capable of x-hydroxylation of fatty acids During the early 1980s, Hansson et al reported on the x-oxidation of leukotriene B4 (LTB4) in human leukocytes [37] The x-oxidation pathway is necessary for the degradation (and thereby inactivation) of this compound, which plays an important role in the inflammation process The CYP450 involved in this pathway belonged to a, at that moment, unidentified subfamily, the CYP4F subfamily (reviewed in [38,39]), and was designated as CYP4F3 Later it was found that the CYP4F3 gene could give rise to two different transcripts by alternative promoter usage and tissue-specific gene splicing, which results in two different proteins [40,41] The isoform originally detected in leukocytes was designated CYP4F3A and the other, which was detected in liver, was designated CYP4F3B These proteins differ from each other due to the alternative use of only one exon However, this leads to a substantial difference in substrate specificity, with CYP4F3A being specific for LTB4, whereas CYP4F3B has a higher specificity towards arachidonic acid [40,42] Shortly after the cloning of CYP4F3A from human leukocytes in 1993, Kikuta et al identified a novel LTB4-hydroxylating CYP450 in human liver [43] This 186 isoform was named CYP4F2 and has a high homology with the CYP4F3B protein CYP4F2 was shown to be the major arachidonic acid x-hydroxylase in human liver and kidney with a higher substrate specificity for arachidonic acid than the already established arachidonic acid x-hydroxylase CYP4A11 [44,45] The formation of x-hydroxylated arachidonic acid (20-hydroxyeicosatetraenoic acid) plays an important role in the regulation of the cardiovascular system because it is a known vasoconstrictor (reviewed in [46]) CYP4F2 was also shown to x-hydroxylate LTB4 in liver, which suggests that this protein might play a role in the inflammatory system [47] Furthermore, CYP4F2 is responsible for x-hydroxylation of the phytyl tail of the tocopherols and tocotrienols that are collectively called vitamin E [48] Omega-hydroxylation is the initial step for the degradation of vitamin E via x-oxidation and subsequent b-oxidation [48,49] Three additional members of the CYP4F subfamily have been identified in humans, as reviewed by Kalsotra and Strobel [38] These were recently discovered and have been only partially characterized CYP4F8 is present in epithelial linings and catalyzes the (x-1)-hydroxylation of prostaglandin H2 CYP4F11 is mainly expressed in liver, followed by kidney, heart, brain and skeletal muscle No endogenous substrates have been found to date for CYP4F11, but it has been shown that recombinant CYP4F11 is quite active in hydroxylating some xenobiotics Finally, the CYP4F12 protein detected in human liver, heart, gastrointestinal and urogenital epithelia is active towards both eicosanoids and xenobiotics Other CYP4 homologs The CYP4B1 protein, which is predominantly expressed in lung, forms another subfamily of x-hydroxylases However, this protein has no clear substrate spectrum, but it is capable of x-hydroxylating medium-chain FAs and xenobiotics (see [50] for review) Other CYP450s belonging to family have been identified in humans Their homology with the known CYP4 subfamilies suggests that these orphans (i.e CYPs with unknown substrate specificity) might be able to x-hydroxylate FAs and ⁄ or FA-like compounds [51] The most important and well-characterized x-hydroxylases, the CYP450s belonging to the CYP4A and 4F subfamilies, are present not only in humans; CYP4A ⁄ F homologs are also well represented in other animals, such as the mouse, rat and rabbit [38,52,53] Moreover, these animals contain more CYP4A and CYP4F subfamily members than humans, which FEBS Journal 278 (2011) 182–194 ª 2010 The Authors Journal compilation ª 2010 FEBS R J A Wanders et al makes interpretation of results found in studies using these animals problematic Induction of fatty acid x-hydroxylases CYP4A gene regulation and the role of peroxisome proliferator-activated receptor a in CYP4A induction The induction of drug-metabolizing enzymes by foreign compounds has been the topic of many research studies during the last several decades Halfway the 20th century it was already known that the x-hydroxylase activity in microsomal fractions prepared from rat livers was much higher when laboratory animals were fed with certain kinds of xenobiotics, including: (a) polycyclic aromatic hydrocarbons and (b) barbiturates, as described in Conney [54] A third type of metabolic enzyme inducers are the hypolipidemic drugs of the fibrate class, which have been in use since the early 1960s, and were found to upregulate the x-hydroxylation of lauric acid [55,56] All of these compounds are able to induce one or more CYP450s However, the precise mechanism which is the basis of this induction has remained unclear for several decades The discovery that a receptor (the aryl or aromatic hydrocarbon receptor) was involved in the induction by polycyclic aromatic hydrocarbons of the CYP450s responsible for the hydroxylation of polycyclic aromatic hydrocarbons (CYP1 family) was the first step in unraveling the complex mechanism of CYP450 regulation (reviewed in [57]) Another breakthrough in CYP450 regulation was the finding that peroxisome proliferator-activated receptor alpha (PPARa) was involved in the induction of CYP4A enzymes (reviewed by Johnson et al [58]) PPARa is a member of the large receptor superfamily of ligand-activated transcription factors (also referred to as the nuclear receptor family) [59] Moreover, many members of this superfamily have been found to be involved in the regulation of multiple CYP450s [60,61] PPARa is a member of the larger family of PPARs which also consists of a b- (d) and c-isoform All isoforms play important roles in physiological processes as lipid sensors and regulators of lipid and glucose homeostasis However, the different PPARs have specific substrate specificities and tissue distributions, and control specific subsets of transcriptional profiles (see [62,63] for review) Activation of the PPARs by the so-called peroxisome proliferators (a structurally unrelated class of compounds among which are FAs, plasticizers, herbicides and the fibrate class of hypolipidemic drugs) enables the receptor to dimerize Fatty acid oxidation disorders with another nuclear receptor, the retinoid X receptor [64] The ligand-activated heterodimer can bind to specific sequences of DNA known as peroxisome proliferator responsive elements in the promoter regions of target genes, thereby inducing gene expression of the target gene Most of these target genes are involved in lipid metabolism Particularly pronounced is the induction of proteins involved in peroxisomal fatty acid metabolism, which leads to an increase in peroxisomal number (i.e peroxisome proliferation) and size [65] Induction of hepatic peroxisome proliferation by PPARa activation in rodents ultimately leads to hepatomegaly and hepatocarcinogenesis (see Gonzalez [66] for review) Fortunately, these toxic effects of PPARa ligands are not observed in humans [67] Therefore, fibrates are still in use as important drugs for the treatment of patients with dyslipidemia and ⁄ or metabolic syndrome (reviewed in [68,69]) Besides increasing peroxisomal FA oxidation, PPARa is also involved in the upregulation of mitochondrial b-oxidation, FA transport and the already mentioned FA x-hydroxylation via the CYP4A subfamily Initial studies, which focused on the induction of the CYP4A subfamily in rats and mice, showed that levels of certain subtypes did indeed increase in these rodent animal models after PPARa activation [70,71] In humans, uncertainties remain with respect to the induction of the CYP4A subtype Overexpression of PPARa in the hepatoma cell line HepG2 led to an increase in CYP4A11 ⁄ A22 under specific growth conditions, suggesting the involvement of PPARa in the regulation of human CYP4A expression [72] Another study showed that fibrates are able to induce CYP4A11 mRNA expression in primary cultures of human hepatocytes [73] By contrast, the peroxisome proliferators responsive elements present in the promotor regions of the genes coding for members of the CYP4A subfamily in rodents have not been identified in human CYP4A genes [36] Recently, another regulatory pathway for CYP4A11 gene expression was discovered Activation of a different member of the nuclear hormone receptor family, retinoic acid receptor, by all-trans retinoic acid (ATRA) in the hepatoma cell line HepaRG was shown to decrease CYP4A11 gene and protein expression, ultimately leading to a decrease in catalytic activity (lauric acid hydroxylation) in this cell line [74] In mice, three different CYP4A genes have been identified Cyp4a10 is highly expressed in both sexes, whereas Cyp4a12 (consisting of two gene products, Cyp4a12a and Cyp4a12b) is predominantly male specific and Cyp4a14 is a female-specific isoform Furthermore, the protein levels of these Cyp4a isoforms vary FEBS Journal 278 (2011) 182–194 ª 2010 The Authors Journal compilation ª 2010 FEBS 187 Fatty acid oxidation disorders R J A Wanders et al in different mouse strains and tissues PPARa also plays an important role in the regulation of the expression of the different Cyp4a isoforms in mice Fibrates are able to induce gene expression of Cyp4a10 and Cyp4a14 [71,75] in both liver and kidney Cyp4a12 is constitutively expressed in kidney and liver of male mice, whereas in kidney and liver of female mice Cyp4a12 is expressed at low levels Moreover, Cyp4a12 gene expression cannot be induced by fibrates in kidney and liver of male mice, whereas in female mice, kidney and liver Cyp4a12 RNA levels were increased to male levels after treatment with fibrates In addition, Cyp4a12 gene expression is also upregulated in female mice by treatment with androgens via an as yet unknown mechanism [75,76] CYP4F induction By contrast to the CYP4A subfamily, relatively few studies have appeared on the regulation of genes comprising the CYP4F subfamily (reviewed in [37,38,77]) Regulation of the CYP4F2 gene has been studied most intensively of all human isoforms Zhang et al [78] found that CYP4F2 gene expression was regulated by retinoic acid and fibrates Peroxisome proliferators suppressed CYP4F2 promotor activity, whereas both 9-cis-retinoic acid and ATRA induced promoter activity through activation of retinoic acid receptor and retinoid X receptor However, further research revealed that protein expression of CYP4F2 was increased by 9-cis-retinoic acid in the hepatoma cell line HepG2, in marked contrast to ATRA, which only gave rise to an induction of CYP4F2 promotor activity [79] From these results, Zhang and Hardwick concluded that CYP4F2 gene expression is regulated by 9-cis-retinoic acid and ATRA Activation of retinoid X receptor induces gene expression (and protein content) and retinoic acid receptor activation results in repression of gene expression Recently, Hsu et al showed that in HepG2 cells and primary hepatocytes, CYP4F2 gene expression and protein content could be induced by statins, which are well-known drugs used for the treatment of hypercholesterolemia [80] Furthermore, Hsu et al showed that the CYP4F2 transcriptional activation is mediated by sterol regulatory element binding proteins (SREBP; reviewed in [81]) and that activation of the sterol regulatory element binding protein-2 isoform is involved in the induction CYP4F2 by statins [80] Parallel studies on the induction of CYP4F3 showed that this enzyme was induced in HL60 cells and human leukocytes after treatment of these cells with 188 ATRA [82,83] However, the mechanism behind this induction remains to be determined since the receptor for ATRA, i.e retinoic acid receptor, seems only indirectly involved in this process Studies in rats and mice have shown that the expression of some isoforms of the CYP4 subfamily changes during inflammation During an inflammatory response, induction of CYP4F isoforms occurs in rodents needed for the breakdown of inflammatory mediators such as the eicosanoid LTB4 (reviewed in [38,77]) Recent studies by Kalsotra et al [84] provided evidence that specific cytokines are involved in regulation of the CYP4F enzymes levels during inflammation The pro-inflammatory cytokines interleukin-1b, interleukin-6 and tumor necrosis factor-a are able to induce CYP4Fs, whereas the anti-inflammatory cytokine interleukin-10 suppresses CYP4F expression [84] Peroxisomal fatty acid b-oxidation disorders including X-ALD and x-oxidation Despite the profound increase in our knowledge about X-ALD, treatment options are very limited and are mostly symptomatic Lorenzo’s oil reduces plasma C26:0 but does not halt progression of the disease [85,86] Lovastatin also lowered plasma VLCFA [87], but a recent placebo-controlled trial revealed that lovastatin has no effect on C26:0 levels in peripheral blood lymphocytes and erythrocytes, or on the VLCFA content of the low-density lipoprotein fraction [88] Hematopoietic stem cell transplantation can halt or reverse clinical deterioration [89] However, it is only effective in patients at the earliest stage of CCALD Recent breakthroughs in gene therapy have to date been applied to CCALD only [25] Therefore new therapeutic options aimed at the reduction of VLCFA are warranted We have previously demonstrated that VLCFA can undergo x-oxidation [90] This would provide an alternative mode of degradation We demonstrated that CYP4F2 and CYP4F3B are key enzymes in this pathway [91] In the first step of the metabolism of VLCFA via x-oxidation, VLCFAs are converted into x-hydroxy-VLCFA by CYP4F2 or CYP4F3B (Fig 1) Subsequently, this product is readily oxidized to a dicarboxylic-VLCFA by an alcohol and aldehyde dehydrogenase or via subsequent hydroxylation reactions by CYP4F2 and CYP4F3B [92] The dicarboxylyl-VLCFAs that are generated can be metabolized further in peroxisomes via b-oxidation Beta-oxidation of dicarboxylyl VLCFA takes place in peroxisomes and this process is not deficient in FEBS Journal 278 (2011) 182–194 ª 2010 The Authors Journal compilation ª 2010 FEBS R J A Wanders et al X-ALD This is concluded from the finding that b-oxidation of long-chain dicarboxylic acid is not affected in fibroblasts from X-ALD patients, whereas oxidation was deficient in fibroblasts from patients with a peroxisomal biogenesis disorder [93] These findings indicate that peroxisomes are essential for the degradation of dicarboxylic acids, but that ALDP is not required for the transport of dicarboxylic acids across the peroxisomal membrane Because the transport of dicarboxylic acids may involve other ABC half-transporters, i.e ALDRP or PMP70, the x-oxidation of VLCFA may function as an escape route Under normal physiological conditions, the x-oxidation pathway accounts for 5–10% of total FA oxidation Because expression levels of cytochrome P450 enzymes can be induced by a variety of drugs and chemicals [94], stimulation of VLCFA x-oxidation may reduce or normalize VLCFA levels and might therefore be beneficial for X-ALD patients (Fig 1) The possibility of upregulating VLCFA x-oxidation and its consequences for VLCFA homeostasis are now being studied in a mouse model of X-ALD Mitochondrial b-oxidation and x-oxidation In the case of mitochondrial FA b-oxidation disorders, there is accumulation of certain FAs either as free Fatty acid oxidation disorders FAs, or in an esterified form as in CoA and carnitine esters The types of FAs and FA derivates that accumulate are determined by the site of the enzyme defect The different acylcarnitine profiles observed in the various mitochondrial b-oxidation deficiencies emphasize this notion [95] Specific induction of the capacity to x-oxidize these FAs would reduce the FA burden and may ameliorate the signs and symptoms in these patients No studies on this point have been published in the literature Refsum disease, phytanic acid and x-oxidation Brenton and Krywawych [96] reported on the excretion of 3-methyladipic acid in the urine of Refsum patients, which suggested that phytanic acid does undergo x-oxidation under in vivo conditions This was soon followed by another report, which documented the identification of 2,6-dimethyloctanedioic acid, a metabolite derived from x-oxidation of phytanic acid in Refsum’s patients The finding by Wierzbicki et al [97] that the amounts of 3-methyladipic acid in urine from Refsum’s patients correlated with plasma levels of phytanic acid in these patients, has lent further support to the notion that 3-methyladipic acid is indeed formed upon x-oxidation of phytanic acid Based on these results, we have begun to characterize the enzymology of the x-oxidation Fig Schematic diagram depicting phytanic acid homeostasis Phytanic acid is derived solely from dietary sources and can be oxidized by either a-oxidation or x-oxidation (see text for further details) The product of the peroxisomal a-oxidation of phytanic acid is pristanic acid which first undergoes three cycles of b-oxidation in the peroxisome to produce propionyl-CoA (in the first and third cycle of b-oxidation) and acetyl-CoA (in the second cycle of b-oxidation) plus 4,8-dimethylnonanoyl-CoA These CoA-esters are all transferred to mitochondria for further oxidation FEBS Journal 278 (2011) 182–194 ª 2010 The Authors Journal compilation ª 2010 FEBS 189 Fatty acid oxidation disorders R J A Wanders et al pathway, first in rat liver microsomes [98] and then in human liver microsomes [99,100] In rat liver microsomes we found that phytanic acid undergoes both (x-) and (x-1)-hydroxylation [98] In human microsomes, however, there was a virtually exclusive production of x-hydroxy phytanic acid [99] In order to identify the CYP450 involved we first performed studies with selective inhibitors including 17-octadecynoic acid, diethyldithiocarbamate, ketoconazole, troleandomycin, omeprazole, trimethoprim, furafylline, quinidine and sulfaphenozole [100] These studies already pointed to the CYP4 family of x-hydroxylases as likely candidates The availability of individually expressed CYP4s produced in baculovirus-infected insect cells (SupersomesÔ) allowed this possibility to be tested directly CYP4F3A turned out to be most reactive towards phytanic acid, followed by CYP4F3B, CYP4F2 and CYP4A11 with catalytic efficiencies of 0.87, 0.22, 0.06 and 0.02, respectively [100] The question now is whether upregulation of one or more of these CYP450s is feasible under in vivo conditions and if this is associated with an increased rate of phytanic acid x-oxidation or not [12] (see Fig 3) With respect to CYP4F3A and CYP4F3B, there is no information about whether expression can be upregulated CYP4A11 expression is controlled by PPARa in conjunction with retinoid X receptor so that fibrates or other PPAR ligands should be successful in upregulating CYP4A11 activity Finally, with respect to CYP4F2, it has been established experimentally that the promoter of the CYP4F2 gene contains a sterol-regulatory element, as described above Activation of the classical sterol regulatory element binding protein (SREBP) route, for example by means of statins, inhibitors of 3-hydroxy3-methylglutaryl-CoA (HMG-CoA) reductase, would then lead to the increased expression of CYP4F2 The availability of a mouse model for Refsum disease allows for future studies aimed at resolving whether upregulation of CYP4A11 by fibrates and ⁄ or CYP4F2 by statins leads to the enhanced degradation of phytanic acid and amelioration of the clinical signs and symptoms [101] Conclusions Omega-oxidation as a rescue pathway for different genetic diseases in humans in which either peroxisomal or mitochondrial FA oxidation is impaired, is an attractive possibility to allow breakdown of FAs which accumulate as a consequence of an enzyme or transporter defect Identification of the specific cytochrome P450s involved in the x-oxidation of phytanic acid and VLCFAs, added to the fact that the different CYPs involved can be induced pharmacologically, now 190 allows us to study whether our in vitro data can be extrapolated successfully to intact organisms We will first perform such studies in mouse models for Refsum disease and X-ALD Acknowledgements This work was supported by grants from the European Leukodystrophy Association [ELA 2008-05111A (RJW)], the Prinses Beatrix Fonds [WAR08-20 (SK)] and the Netherlands Organization for Scientific Research [VIDI-grant No 91786328 (SK)] Mrs 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FAs lauric acid, myristic acid (tetradecanoic acid) , palmitic acid (hexadecanoic acid) and the unsaturated FAs oleic acid [(Z)-octadec-9-enoic acid] and arachidonic acid (all-cis-5,8,11,14-eicosatetraenoic... Mitochondrial b -oxidation and x -oxidation In the case of mitochondrial FA b -oxidation disorders, there is accumulation of certain FAs either as free Fatty acid oxidation disorders FAs, or in an esterified... which involves carnitine palmitoyltransferase I, mitochondrial carnitine acylcarnitine translocase and carnitine palmitoyltransferase II [5–7] In case of the straight-chain and 2-methyl-branched