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• W2159242199 abstract "Branched-chain fatty acids (such as phytanic and pristanic acid) are ligands for the nuclear hormone receptor peroxisome proliferator-activated receptor α (PPARα) in vitro. To investigate the effects of these physiological compounds in vivo, wild-type and PPARα-deficient (PPARα−/−) mice were fed a phytol-enriched diet. This resulted in increased plasma and liver levels of the phytol metabolites phytanic and pristanic acid. In wild-type mice, plasma fatty acid levels decreased after phytol feeding, whereas in PPARα−/− mice, the already elevated fatty acid levels increased. In addition, PPARα−/− mice were found to be carnitine deficient in both plasma and liver. Dietary phytol increased liver free carnitine in wild-type animals but not in PPARα−/− mice. Investigation of carnitine biosynthesis revealed that PPARα is likely involved in the regulation of carnitine homeostasis. Furthermore, phytol feeding resulted in a PPARα-dependent induction of various peroxisomal and mitochondrial β-oxidation enzymes. In addition, a PPARα-independent induction of catalase, phytanoyl-CoA hydroxylase, carnitine octanoyltransferase, peroxisomal 3-ketoacyl-CoA thiolase, and straight-chain acyl-CoA oxidase was observed.In conclusion, branched-chain fatty acids are physiologically relevant ligands of PPARα in mice. These findings are especially relevant for disorders in which branched-chain fatty acids accumulate, such as Refsum disease and peroxisome biogenesis disorders. Branched-chain fatty acids (such as phytanic and pristanic acid) are ligands for the nuclear hormone receptor peroxisome proliferator-activated receptor α (PPARα) in vitro. To investigate the effects of these physiological compounds in vivo, wild-type and PPARα-deficient (PPARα−/−) mice were fed a phytol-enriched diet. This resulted in increased plasma and liver levels of the phytol metabolites phytanic and pristanic acid. In wild-type mice, plasma fatty acid levels decreased after phytol feeding, whereas in PPARα−/− mice, the already elevated fatty acid levels increased. In addition, PPARα−/− mice were found to be carnitine deficient in both plasma and liver. Dietary phytol increased liver free carnitine in wild-type animals but not in PPARα−/− mice. Investigation of carnitine biosynthesis revealed that PPARα is likely involved in the regulation of carnitine homeostasis. Furthermore, phytol feeding resulted in a PPARα-dependent induction of various peroxisomal and mitochondrial β-oxidation enzymes. In addition, a PPARα-independent induction of catalase, phytanoyl-CoA hydroxylase, carnitine octanoyltransferase, peroxisomal 3-ketoacyl-CoA thiolase, and straight-chain acyl-CoA oxidase was observed. In conclusion, branched-chain fatty acids are physiologically relevant ligands of PPARα in mice. These findings are especially relevant for disorders in which branched-chain fatty acids accumulate, such as Refsum disease and peroxisome biogenesis disorders. Peroxisome proliferator-activated receptor α (PPARα) is one of the PPARs that form a subfamily of the nuclear hormone receptor superfamily. PPARs are ligand-activated transcription factors: after ligand binding, PPARs heterodimerize with the retinoic X receptor α and modulate the expression of target genes by binding to specific peroxisome proliferator response elements in the promotor region of regulated genes (1Berger J. Moller D.E. The mechanisms of action of PPARs.Annu. Rev. Med. 2002; 53: 409-435Crossref PubMed Scopus (2064) Google Scholar). Three PPAR isoforms are known: PPARα, PPARβ, and PPARγ. The three isoforms have different tissue distributions and functions. PPARα is mostly expressed in organs with a high rate of fatty acid catabolism, such as brown adipose tissue, liver, kidney, and heart, and it plays an important role in various aspects of lipid and glucose metabolism (2Reddy J.K. Hashimoto T. Peroxisomal beta-oxidation and peroxisome proliferator-activated receptor alpha: an adaptive metabolic system.Annu. Rev. Nutr. 2001; 21: 193-230Crossref PubMed Scopus (727) Google Scholar, 3Braissant O. Foufelle F. Scotto C. Dauca M. Wahli W. Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat.Endocrinology. 1996; 137: 354-366Crossref PubMed Scopus (1710) Google Scholar).PPARα has a broad range of both artificial and natural ligands also called peroxisome proliferators. The artificial ligands of PPARα consist of a variety of compounds, including hypolipidemic drugs (e.g., clofibrate and Wy-14,643), phthalate ester plasticizers, herbicides, and several chlorinated hydrocarbons. A broad array of unsaturated fatty acids, but also long-chain fatty acids and branched-chain fatty acids (e.g., phytanic acid), are natural ligands for PPARα (4Ellinghaus P. Wolfrum C. Assmann G. Spener F. Seedorf U. Phytanic acid activates the peroxisome proliferator-activated receptor alpha (PPARalpha) in sterol carrier protein 2-/sterol carrier protein x-deficient mice.J. Biol. Chem. 1999; 274: 2766-2772Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar, 5Moya-Camarena S.Y. van den Heuvel J.P. Blanchard S.G. Leesnitzer L.A. Belury M.A.A. Conjugated linoleic acid is a potent naturally occurring ligand and activator of PPARalpha.J. Lipid Res. 1999; 40: 1426-1433Abstract Full Text Full Text PDF PubMed Google Scholar, 6Zomer A.W. van der Burg B. Jansen G.A. Wanders R.J. Poll-The B.T. van der Saag P.T.T. Pristanic acid and phytanic acid: naturally occurring ligands for the nuclear receptor peroxisome proliferator-activated receptor alpha.J. Lipid Res. 2000; 41: 1801-1807Abstract Full Text Full Text PDF PubMed Google Scholar, 7Forman B.M. Chen J. Evans R.M. Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta.Proc. Natl. Acad. Sci. USA. 1997; 94: 4312-4317Crossref PubMed Scopus (1850) Google Scholar, 8Kliewer S.A. Sundseth S.S. Jones S.A. Brown P.J. Wisely G.B. Koble C.S. Devchand P. Wahli W. Willson T.M. Lenhard J.M. Lehmann J.M.M. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma.Proc. Natl. Acad. Sci. USA. 1997; 94: 4318-4323Crossref PubMed Scopus (1871) Google Scholar). Administration of peroxisome proliferators to rodents results in hepatomegaly and an increase in the number and size of peroxisomes. In addition, it changes the expression of a variety of genes involved in various aspects of lipid metabolism, ranging from fatty acid transport and mitochondrial and peroxisomal fatty acid β-oxidation to microsomal fatty acid ω-oxidation. Chronic treatment of rodents with peroxisome proliferators results in hepatocellular carcinomas (9Gonzalez F.J. The peroxisome proliferator-activated receptor alpha (PPARalpha): role in hepatocarcinogenesis.Mol. Cell. Endocrinol. 2002; 193: 71-79Crossref PubMed Scopus (56) Google Scholar). These changes are all mediated by PPARα, as demonstrated by studies with PPARα-deficient (PPARα−/−) mice. Under normal conditions, PPARα−/− mice are indistinguishable from wild-type animals and have normal levels of hepatic peroxisomes. Upon fasting, however, PPARα−/− mice are unable to switch to fatty acid oxidation; they develop a fatty liver and become severely hypoglycemic (10Hashimoto T. Cook W.S. Qi C. Yeldandi A.V. Reddy J.K. Rao M.S.S. Defect in peroxisome proliferator-activated receptor alpha-inducible fatty acid oxidation determines the severity of hepatic steatosis in response to fasting.J. Biol. Chem. 2000; 275: 28918-28928Abstract Full Text Full Text PDF PubMed Scopus (345) Google Scholar). Similarly, feeding these mice a high-fat diet results in massive accumulation of lipids in the liver, attributable to their inability to enhance fatty acid degradation (11Kersten S. Seydoux J. Peters J.M. Gonzalez F.J. Desvergne B. Wahli W.W. Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting.J. Clin. Invest. 1999; 103: 1489-1498Crossref PubMed Scopus (1345) Google Scholar). PPARα−/− mice do display an altered constitutive expression of several mitochondrial and peroxisomal enzymes involved in the oxidation of fatty acids (12Aoyama T. Peters J.M. Iritani N. Nakajima T. Furihata K. Hashimoto T. Gonzalez F.J.J. Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor alpha (PPARalpha).J. Biol. Chem. 1998; 273: 5678-5684Abstract Full Text Full Text PDF PubMed Scopus (744) Google Scholar). However, PPARα−/− mice are nonresponsive to treatment with peroxisome proliferators; hence, they do not show any physiological, toxicological, or carcinogenic responses to peroxisome proliferators (13Lee S.S. Pineau T. Drago J. Lee E.J. Owens J.W. Kroetz D.L. Fernandez-Salguero P.M. Westphal H. Gonzalez F.J.J. Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators.Mol. Cell. Biol. 1995; 15: 3012-3022Crossref PubMed Scopus (1492) Google Scholar).In the studies mentioned above, artificial ligands such as clofibrate and Wy-14,643 were used as PPARα ligands. Relatively little is known about the effects of natural PPARα ligands, such as the branched-chain fatty acids phytanic and pristanic acid, which have been shown to activate PPARα in vitro, in contrast to their precursor phytol (6Zomer A.W. van der Burg B. Jansen G.A. Wanders R.J. Poll-The B.T. van der Saag P.T.T. Pristanic acid and phytanic acid: naturally occurring ligands for the nuclear receptor peroxisome proliferator-activated receptor alpha.J. Lipid Res. 2000; 41: 1801-1807Abstract Full Text Full Text PDF PubMed Google Scholar, 14Heim M. Johnson J. Boess F. Bendik I. Weber P. Hunziker W. Fluhmann B.B. Phytanic acid, a natural peroxisome proliferator-activated receptor (PPAR) agonist, regulates glucose metabolism in rat primary hepatocytes.FASEB J. 2002; 16: 718-720Crossref PubMed Scopus (102) Google Scholar). Phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) is derived from the chlorophyll component phytol and undergoes α-oxidation in the peroxisome, which leads to shortening of the chain by one carbon atom, yielding pristanic acid (2,6,10,14-tetramethylpentadecanoic acid) and carbon dioxide. Pristanic acid is then further degraded in the peroxisome via β-oxidation (15Mukherji M. Schofield C.J. Wierzbicki A.S. Jansen G.A. Wanders R.J. Lloyd M.D.D. The chemical biology of branched-chain lipid metabolism.Prog. Lipid Res. 2003; 42: 359-376Crossref PubMed Scopus (67) Google Scholar). In patients affected by different peroxisomal disorders, there is an accumulation of phytanic and/or pristanic acid. Patients suffering from Refsum disease have a deficiency of phytanoyl-CoA hydroxylase (PhyH), the first enzyme of the α-oxidation system, and as a consequence accumulate phytanic acid in tissues and plasma (16Wanders R.J. Jansen G.A. Skjeldal O.H. Refsum disease, peroxisomes and phytanic acid oxidation: a review.J. Neuropathol. Exp. Neurol. 2001; 60: 1021-1031Crossref PubMed Scopus (67) Google Scholar). In α-methylacyl-CoA racemase (AMACR) or d-bifunctional protein (DBP) deficiency, two enzymes involved in the peroxisomal β-oxidation of branched-chain fatty acids, there is an accumulation of pristanic acid. Patients suffering from a peroxisome biogenesis disorder accumulate both phytanic and pristanic acid because they are deficient in both peroxisomal α- and β-oxidation (reviewed in 17Wanders R.J. van Roermund C.W. Visser W.F. Ferdinandusse S. Jansen G.A. van den Brink D.M. Gloerich J. Waterham H.R.R. Peroxisomal fatty acid alpha- and beta-oxidation in health and disease: new insights.Adv. Exp. Med. Biol. 2003; 544: 293-302Crossref PubMed Scopus (16) Google Scholar).In this study, we investigated the effects of the accumulation of these branched-chain fatty acids by feeding mice a diet enriched with phytol. Thus, we mimicked the situation in patients suffering from a peroxisomal disorder, because this results in an increase of phytol metabolites in tissues and plasma (4Ellinghaus P. Wolfrum C. Assmann G. Spener F. Seedorf U. Phytanic acid activates the peroxisome proliferator-activated receptor alpha (PPARalpha) in sterol carrier protein 2-/sterol carrier protein x-deficient mice.J. Biol. Chem. 1999; 274: 2766-2772Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar, 18Atshaves B.P. Payne H.R. McIntosh A.L. Tichy S.E. Russell D. Kier A.B. Schroeder F.F. Sexually dimorphic metabolism of branched-chain lipids in C57BL6/6J mice.J. Lipid Res. 2004; 45: 812-830Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar). In several mouse models for peroxisomal β-oxidation disorders in which branched-chain fatty acids are increased, an altered expression of various fatty acid-metabolizing enzymes has been reported (19Baes M. Huyghe S. Carmeliet P. Declercq P.E. Collen D. Mannaerts G.P. van Veldhoven P.P.P. Inactivation of the peroxisomal multifunctional protein-2 in mice impedes the degradation of not only 2-methyl-branched fatty acids and bile acid intermediates but also of very long chain fatty acids.J. Biol. Chem. 2000; 275: 16329-16336Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar, 20Seedorf U. Raabe M. Ellinghaus P. Kannenberg F. Fobker M. Engel T. Denis S. Wouters F. Wirtz K.W. Wanders R.J. Maeda N. Assmann G.G. Defective peroxisomal catabolism of branched fatty acyl coenzyme A in mice lacking the sterol carrier protein-2/sterol carrier protein-x gene function.Genes Dev. 1998; 12: 1189-1201Crossref PubMed Scopus (243) Google Scholar, 21Fan C.Y. Pan J. Chu R. Lee D. Kluckman K.D. Usuda N. Singh I. Yeldandi A.V. Rao M.S. Maeda N. Reddy J.K.K. Hepatocellular and hepatic peroxisomal alterations in mice with a disrupted peroxisomal fatty acyl-coenzyme A oxidase gene.J. Biol. Chem. 1996; 271: 24698-24710Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar, 22Savolainen K. Kotti T.J. Schmitz W. Savolainen T.I. Sormunen R.T. Ilves M. Vainio S.J. Conzelmann E. Hiltunen J.K.K. A mouse model for {alpha}-methylacyl-CoA racemase deficiency: adjustment of bile acid synthesis and intolerance to dietary methyl-branched lipids.Hum. Mol. Genet. 2004; 13: 955-965Crossref PubMed Scopus (69) Google Scholar).We studied the expression of both peroxisomal and mitochondrial proteins involved in the metabolism of fatty acids in wild-type and PPARα−/− mice after phytol feeding. Furthermore, we investigated the effect of a phytol diet on the levels of various metabolites in plasma and liver, including very long-chain, branched-chain, and polyunsaturated fatty acids, acylcarnitines, and carnitine biosynthesis intermediates.MATERIALS AND METHODSAnimalsMale wild-type and PPARα−/− mice on a Sv/129 genetic background were used for this study (13Lee S.S. Pineau T. Drago J. Lee E.J. Owens J.W. Kroetz D.L. Fernandez-Salguero P.M. Westphal H. Gonzalez F.J.J. Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators.Mol. Cell. Biol. 1995; 15: 3012-3022Crossref PubMed Scopus (1492) Google Scholar). Six week old wild-type and PPARα−/− mice were fed pelleted mouse chow (Hope Farms, Woerden, The Netherlands) containing no (control) or 0.5% (w/w) phytol for 1, 2, 4, or 8 weeks. Each group consisted of three animals. At the end of the experiment, mice were anesthetized using isoflurane, blood was collected by cardiac puncture, and tissues were harvested. The animals were always killed at the same time of day, and animals had free access to water and food until that moment. Tissues were snap-frozen in liquid nitrogen and stored at −80°C until further analysis. A small piece of tissue was treated immediately with RNAlater RNA stabilization reagent (Qiagen, Venlo, The Netherlands) according to the manufacturer's instructions and stored at −80°C until RNA isolation. All animal experiments were approved by the University of Amsterdam Animals Experiments Committee.Metabolite analysis in plasma and liverTotal very long-chain fatty acids (VLCFAs) up to 26 carbon atoms and branched-chain fatty acids in plasma and liver were analyzed using GC-MS (23Vreken P. van Lint A.E. Bootsma A.H. Overmars H. Wanders R.J. van Gennip A.H.H. Rapid stable isotope dilution analysis of very-long-chain fatty acids, pristanic acid and phytanic acid using gas chromatography-electron impact mass spectrometry.J. Chromatogr. B Biomed. Sci. Appl. 1998; 713: 281-287Crossref PubMed Scopus (80) Google Scholar). Total fatty acids with more than 26 carbon atoms were analyzed using electrospray ionization (ESI)-tandem MS (24Valianpour F. Selhorst J.J. van Lint L.E. van Gennip A.H. Wanders R.J. Kemp S.S. Analysis of very long-chain fatty acids using electrospray ionization mass spectrometry.Mol. Genet. Metab. 2003; 79: 189-196Crossref PubMed Scopus (113) Google Scholar). Because some of the necessary standards for precise quantitative analysis of these extremely long-chain fatty acids are not commercially available, only a comparative analysis between the different groups could be performed. For this reason, the amount of each fatty acid present in wild-type mice fed a control diet was set to 1. Total polyunsaturated fatty acids in plasma were measured by GC analysis (25Dacremont G. Vincent G. Assay of plasmalogens and polyunsaturated fatty acids (PUFA) in erythrocytes and fibroblasts.J. Inherit. Metab. Dis. 1995; 18: 84-89Crossref PubMed Scopus (61) Google Scholar). Free carnitine and acylcarnitines in plasma and liver were analyzed as their propyl esters using ESI-tandem MS as described previously (26Vreken P. van Lint A.E. Bootsma A.H. Overmars H. Wanders R.J. van Gennip A.H.H. Quantitative plasma acylcarnitine analysis using electrospray tandem mass spectrometry for the diagnosis of organic acidaemias and fatty acid oxidation defects.J. Inherit. Metab. Dis. 1999; 22: 302-306Crossref PubMed Scopus (116) Google Scholar). The carnitine biosynthesis intermediates trimethyllysine (TML) and γ-butyrobetaine (BB) in plasma and liver were analyzed using ESI-tandem MS (27Van Vlies N. Tian L. Overmars H. Bootsma A.H. Kulik W. Wanders R.J. Wood P.A. Vaz F.M.M. Characterization of carnitine and fatty acid metabolism in the long-chain acyl-CoA dehydrogenase deficient mouse.Biochem. J. 2004; In pressGoogle Scholar).Phytol levels were determined in freshly prepared liver homogenates in PBS. As an internal standard, 1 nmol of C19-OH dissolved in ethanol was added to samples containing 0.5 mg of liver protein. Subsequently, samples were subjected to alkaline hydrolysis by adding 2 ml of 1 M NaOH in methanol and incubated for 45 min at 110°C. After cooling to room temperature, the pH was decreased by adding 480 μl of 37% HCl. Phytol was then extracted with 2 ml of hexane. The organic layer was evaporated to dryness under nitrogen at 40°C. Samples were dissolved in 0.5 ml of heptane and purified on a silica gel column (J. T. Baker, Philipsburg, NJ) using 92:8 heptane-diethyl ether as eluent. Samples were evaporated to dryness under nitrogen at 40°C and derivatized with N-methyl-N-(tert-butyldimethylsilyl)trifluoroacetamide (Pierce, Rockford, IL) and pyridine (50 μl each) at 80°C for 30 min. Samples were evaporated to dryness under nitrogen at 40°C, dissolved in 100 μl of hexane, and subjected to GC-MS analysis, essentially as described previously (28Van den Brink D.M. van Miert J.M. Wanders R.J. Assay for Sjogren-Larsson syndrome based on a deficiency of phytol degradation.Clin. Chem. 2005; 51: 240-242Crossref PubMed Scopus (11) Google Scholar). The [M-57]+ ions of phytol and C19-OH (corresponding to 353.3 and 341.3, respectively) were detected. The metabolites were quantified using a calibration curve of phytol.Quantitative real-time RT-PCR analysisTotal RNA was isolated from RNAlater -treated mouse liver and kidney samples using Trizol (Invitrogen, Carlsbad, CA) extraction, after which cDNA was prepared using a first-strand cDNA synthesis kit for RT-PCR (Roche, Mannheim, Germany). Quantitative real-time PCR analysis of long-chain fatty acid elongases 2, 3, and 4 (Elovl2/3/4) and β-actin in liver and/or kidney was performed using the LightCycler FastStart DNA Master SYBR Green I kit (Roche). The following primers were used. For Elovl2: forward, 5′-CACCTTCCTTCATGTCTATCAC-3′; reverse, 5′-GAACAGGATGACCAGCGTCAT-3′. For Elovl3: forward, 5′-CAACAGTGATGTTTACAGTGGGC-3′; reverse, 5′-CATCTGCAGAATCTGCAGGCTG-3′. For Elovl4: forward, 5′-CAACCAAGTCTCCTTCCTTCAC-3′; reverse, 5′-GACAGTGCTGTGTGTCCGATG-3′. Primers for β-actin were used as described (29Sousa M.M. Yan S. Du Fernandes R. Guimaraes A. Stern D. Saraiva M.J.J. Familial amyloid polyneuropathy: receptor for advanced glycation end products-dependent triggering of neuronal inflammatory and apoptotic pathways.J. Neurosci. 2001; 21: 7576-7586Crossref PubMed Google Scholar). Melting curve analysis was carried out to confirm the generation of a single product. Amplification of a single product of the correct size was also confirmed by agarose gel electrophoresis. Duplicate analyses were performed for all samples. Data were analyzed using linear regression calculations as described by Ramakers et al. (30Ramakers C. Ruijter J.M. Deprez R.H. Moorman A.F. Assumption-free analysis of quantitative real-time polymerase chain reaction (PCR) data.Neurosci. Lett. 2003; 339: 62-66Crossref PubMed Scopus (2859) Google Scholar). To adjust for variations in the amount of input RNA, the values for Elovl2, Elovl3, and Elovl4 were normalized against the values for the housekeeping gene β-actin.Immunoblot analysisSmall pieces of liver were homogenized in PBS containing a cocktail of protease inhibitors (Roche, Basel, Switzerland). Ten micrograms of liver homogenate was separated on a 10% (w/v) SDS-polyacrylamide gel and transferred to a nitrocellulose membrane (Schleicher and Shuell, Keene, NH) (31Laemmli U.K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4.Nature. 1970; 227: 680-685Crossref PubMed Scopus (206048) Google Scholar). After blocking of nonspecific binding sites with 30 g/l Protifar (Nutricia, Zoetermeer, The Netherlands) and 10 g/l BSA in 1 g/l Tween-20/PBS, the blot was incubated with specific primary antibodies. Secondary antibodies conjugated to alkaline phosphatase (Bio-Rad, Hercules, CA) were used for detection. Polyclonal antibodies directed against peroxisomal straight-chain acyl-CoA oxidase (SCOX), l-bifunctional protein (LBP), DBP, peroxisomal 3-ketoacyl-CoA thiolase (THIO), sterol carrier protein x (SCPx), PhyH, peroxisomal membrane protein 70 (PMP70) (Zymed, San Francisco, CA), carnitine octanoyltransferase (COT), catalase, short-chain acyl-CoA dehydrogenase (SCAD), medium-chain acyl-CoA dehydrogenase (MCAD), long-chain acyl-CoA dehydrogenase (LCAD), mitochondrial trifunctional protein α subunit (MTPα), short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD), short branched-chain 3-hydroxyacyl-CoA dehydrogenase (SBCHAD), and cytochrome P450 hydroxylase 4A1 (CYP4A1) (BD Gentest, Bedford, MA) were used according to the manufacturer's instructions or as described earlier (12Aoyama T. Peters J.M. Iritani N. Nakajima T. Furihata K. Hashimoto T. Gonzalez F.J.J. Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor alpha (PPARalpha).J. Biol. Chem. 1998; 273: 5678-5684Abstract Full Text Full Text PDF PubMed Scopus (744) Google Scholar, 32Jansen G.A. Ofman R. Denis S. Ferdinandusse S. Hogenhout E.M. Jakobs C. Wanders R.J.J. Phytanoyl-CoA hydroxylase from rat liver. Protein purification and cDNA cloning with implications for the subcellular localization of phytanic acid alpha-oxidation.J. Lipid Res. 1999; 40: 2244-2254Abstract Full Text Full Text PDF PubMed Google Scholar, 33Jiang L.L. Miyazawa S. Hashimoto T. Purification and properties of rat d-3-hydroxyacyl-CoA dehydratase: d-3-hydroxyacyl-CoA dehydratase/d-3-hydroxyacyl-CoA dehydrogenase bifunctional protein.J. Biochem. (Tokyo). 1996; 120: 633-641Crossref PubMed Scopus (39) Google Scholar, 34Tager J.M. van der Beek W.A. Wanders R.J. Hashimoto T. Heymans H.S. van den Bosch H. Schutgens R.B. Schram A.W.W. Peroxisomal beta-oxidation enzyme proteins in the Zellweger syndrome.Biochem. Biophys. Res. Commun. 1985; 126: 1269-1275Crossref PubMed Scopus (87) Google Scholar, 35Wanders R.J. Dekker C. Ofman R. Schutgens R.B. Mooijer P. Immunoblot analysis of peroxisomal proteins in liver and fibroblasts from patients.J. Inherit. Metab. Dis. 1995; 18: 101-112Crossref PubMed Scopus (28) Google Scholar, 36Ossendorp B.C. Voorhout W.F. Amerongen A. van Brunink F. Batenburg J.J. Wirtz K.W.W. Tissue-specific distribution of a peroxisomal 46-kDa protein related to the 58-kDa protein (sterol carrier protein x; sterol carrier protein 2/3-oxoacyl-CoA thiolase).Arch. Biochem. Biophys. 1996; 334: 251-260Crossref PubMed Scopus (30) Google Scholar). Densitometric analysis of the immunoblots was performed using Scion Image software (version β3b).Enzyme activity measurementsAll enzyme activity measurements were done in freshly prepared liver homogenates.Acyl-CoA oxidase activity measurements were performed spectrophotometrically, essentially as described previously (37Wanders R.J. Denis S. Dacremont G. Studies on the substrate specificity of the inducible and non-inducible acyl-CoA oxidases from rat kidney peroxisomes.J. Biochem. (Tokyo). 1993; 113: 577-582Crossref PubMed Scopus (18) Google Scholar). Reactions were started with 50 μM palmitoyl-CoA and 50 μM pristanoyl-CoA for measurement of SCOX and branched-chain acyl-CoA oxidase (BCOX), respectively. DBP and SCPx activities were measured in a combined assay as described (38Ferdinandusse S. Denis S. Berkel E. van Dacremont G. Wanders R.J.J. Peroxisomal fatty acid oxidation disorders and 58 kDa sterol carrier protein X (SCPx). Activity measurements in liver and fibroblasts using a newly developed method.J. Lipid Res. 2000; 41: 336-342Abstract Full Text Full Text PDF PubMed Google Scholar) with the exception that endogenous DBP was used to produce the substrate for SCPx. SCAD, MCAD, and very long-chain acyl-CoA dehydrogenase (VLCAD) activity measurements were performed using HPLC analysis (39Wanders R.J. Vreken P. den Boer M.E. Wijburg F.A. van Gennip A.H. Jlst L.I.I. Disorders of mitochondrial fatty acyl-CoA beta-oxidation.J. Inherit. Metab. Dis. 1999; 22: 442-487Crossref PubMed Scopus (226) Google Scholar). Reactions were started using 25 μM butyryl-CoA, 200 μM 3-phenylpropionyl-CoA, and 250 μM palmitoyl-CoA, respectively. LCAD activity measurements were performed spectrophotometrically as described previously (40Lehman T.C. Hale D.E. Bhala A. Thorpe C. An acyl-coenzyme A dehydrogenase assay utilizing the ferricenium ion.Anal. Biochem. 1990; 186: 280-284Crossref PubMed Scopus (217) Google Scholar, 41Wanders R.J. Denis S. Ruiter J.P. Jlst L.I. Dacremont G. 2,6-Dimethylheptanoyl-CoA is a specific substrate for long-chain acyl-CoA dehydrogenase (LCAD): evidence for a major role of LCAD in branched-chain fatty acid oxidation.Biochim. Biophys. Acta. 1998; 1393: 35-40Crossref PubMed Scopus (36) Google Scholar) using 200 μM 2,6-dimethylheptanoyl-CoA as substrate. Carnitine acetyltransferase (CAT) activity measurements were performed using radiolabeled substrate as described (42Ferdinandusse S. Mulders J. Jlst L.I. Denis S. Dacremont G. Waterham H.R. Wanders R.J.J. Molecular cloning and expression of human carnitine octanoyltransferase: evidence for its role in the peroxisomal beta-oxidation of branched-chain fatty acids.Biochem. Biophys. Res. Commun. 1999; 263: 213-218Crossref PubMed Scopus (54) Google Scholar). Carnitine palmitoyltransferase 2 (CPT2) activity measurements were performed using HPLC analysis, essentially as described by Slama et al. (43Slama A. Brivet M. Boutron A. Legrand A. Saudubray J.M. Demaugre F.F. Complementation analysis of carnitine palmitoyltransferase I and II defects.Pediatr. Res. 1996; 40: 542-546Crossref PubMed Scopus (10) Google Scholar). Catalase activity was measured spectrophotometrically (44Van Kuilenburg A.B. Lenthe H. van Wanders R.J. van Gennip A.H.H. Subcellular localization of dihydropyrimidine dehydrogenase.Biol. Chem. 1997; 378: 1047-1053Crossref PubMed Scopus (13) Google Scholar). Trimethyllysine dioxygenase, trimethylaminobutyraldehyde dehydrogenase (TMABADH), and γ-butyrobetaine dioxygenase (BBD) activities were measured using ESI-tandem MS, as will be described elsewhere (N. Van Vlies, R. J. A. Wanders, and F. M. Vaz, unpublished data).Statistical analysesData are expressed as means ± SD. Statistical significance was evaluated using an unpaired Student's t-test. The results were considered significant at P < 0.01.RESULTSAnalysis of phytol and its metabolites phytenic, phytanic, and pristanic acid in plasma and liverBranched-chain fatty acids were measured in liver and plasma to establish the extent of the accumulation of these phytol metabolites after the phytol-enriched diet (Table 1). In liver from phytol-fed animals, there was a marked increase in hepatic levels of phytenic, phytanic, and pristanic acid. The levels increased with an increasing diet period, but strikingly, the increase was much stronger in wild-type animals than in PPARα−/− mice. These results led us to investigate hepatic phytol levels. Interestingly, we found that there was a greater accumulation of phytol in PPARα−/− mice than in wild-type animals, suggesting a PPARα-dependent upregulation of the breakdown pathway of phytol to phytanic acid in wild-type animals upon phytol feeding. Remarkably, the plasma levels of phytenic, phytanic, and pristanic acid were increased after" @default.
• W2159242199 created "2016-06-24" @default.
• W2159242199 creator A5007182203 @default.
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• W2159242199 title "A phytol-enriched diet induces changes in fatty acid metabolism in mice both via PPARα-dependent and -independent pathways" @default.
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