Lorenzo's oil inhibits ELOVL1 and lowers the level of sphingomyelin with a saturated very long-chain fatty acid

Abstract

X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder caused by impaired degradation of very long-chain fatty acids (VLCFAs) due to mutations in the ABCD1 gene responsible for VLCFA transport into peroxisomes. Lorenzo's oil, a 4:1 mixture of glyceryl trioleate and glyceryl trierucate, has been used to reduce the saturated VLCFA level in the plasma of X-ALD patients; however, the mechanism by which this occurs remains elusive. We report the biochemical characterization of Lorenzo's oil activity toward elongation of very long-chain fatty acid (ELOVL) 1, the primary enzyme responsible for the synthesis of saturated and monounsaturated VLCFAs. Oleic and erucic acids inhibited ELOVL1, and, moreover, their 4:1 mixture (the FA composition of Lorenzo's oil) exhibited the most potent inhibitory activity. The kinetics analysis revealed that this was a mixed (not a competitive) inhibition. At the cellular level, treatment with the 4:1 mixture reduced the level of SM with a saturated VLCFA accompanied by an increased level of SM with a monounsaturated VLCFA, probably due to the incorporation of erucic acid into the FA elongation cycle. These results suggest that inhibition of ELOVL1 may be an underlying mechanism by which Lorenzo's oil exerts its action. X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder caused by impaired degradation of very long-chain fatty acids (VLCFAs) due to mutations in the ABCD1 gene responsible for VLCFA transport into peroxisomes. Lorenzo's oil, a 4:1 mixture of glyceryl trioleate and glyceryl trierucate, has been used to reduce the saturated VLCFA level in the plasma of X-ALD patients; however, the mechanism by which this occurs remains elusive. We report the biochemical characterization of Lorenzo's oil activity toward elongation of very long-chain fatty acid (ELOVL) 1, the primary enzyme responsible for the synthesis of saturated and monounsaturated VLCFAs. Oleic and erucic acids inhibited ELOVL1, and, moreover, their 4:1 mixture (the FA composition of Lorenzo's oil) exhibited the most potent inhibitory activity. The kinetics analysis revealed that this was a mixed (not a competitive) inhibition. At the cellular level, treatment with the 4:1 mixture reduced the level of SM with a saturated VLCFA accompanied by an increased level of SM with a monounsaturated VLCFA, probably due to the incorporation of erucic acid into the FA elongation cycle. These results suggest that inhibition of ELOVL1 may be an underlying mechanism by which Lorenzo's oil exerts its action. FAs are the major constituents of cellular lipids and are highly diverse in their chain length and degree of saturation. This structural diversity underlies the various functions of FAs. The most abundant cellular FAs are long-chain fatty acids (LCFAs) having a chain length of 11 to 20 carbons (C11–C20). FAs with >C20 are called very long-chain fatty acids (VLCFAs) and have essential physiological functions that cannot be compensated for by LCFAs, such as skin barrier formation, retinal function, myelin maintenance, and spermatogenesis (1Agbaga M.P. Mandal M.N. Anderson R.E. Retinal very long-chain PUFAs: new insights from studies on ELOVL4 protein.J. Lipid Res. 2010; 51: 1624-1642Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar, 2Imgrund S. Hartmann D. Farwanah H. Eckhardt M. Sandhoff R. Degen J. Gieselmann V. Sandhoff K. Willecke K. Adult ceramide synthase 2 (CERS2)-deficient mice exhibit myelin sheath defects, cerebellar degeneration, and hepatocarcinomas.J. Biol. Chem. 2009; 284: 33549-33560Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar, 3Vasireddy V. Uchida Y. Salem N. Kim S.Y. Mandal M.N. Reddy G.B. Bodepudi R. Alderson N.L. Brown J.C. Hama H. et al.Loss of functional ELOVL4 depletes very long-chain fatty acids (≥C28) and the unique ω-O-acylceramides in skin leading to neonatal death.Hum. Mol. Genet. 2007; 16: 471-482Crossref PubMed Scopus (202) Google Scholar, 4Zadravec D. Tvrdik P. Guillou H. Haslam R. Kobayashi T. Napier J.A. Capecchi M.R. Jacobsson A. ELOVL2 controls the level of n-6 28:5 and 30:5 fatty acids in testis, a prerequisite for male fertility and sperm maturation in mice.J. Lipid Res. 2011; 52: 245-255Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar, 5Kihara A. Very long-chain fatty acids: elongation, physiology and related disorders.J. Biochem. 2012; 152: 387-395Crossref PubMed Scopus (241) Google Scholar). VLCFAs are components of the two important lipid classes, glycerolipids and sphingolipids, which are characterized by their lipid backbone that in the former is a glycerol and in the latter a sphingoid base. Although the sphingoid base is structurally similar to the glycerol with an FA at the sn-1 position, VLCFAs linked to these backbones are strikingly different: Those of glycerolipids are mostly polyunsaturated, whereas those of sphingolipids are saturated and monounsaturated (especially C24). In mammals, a polar head group, phosphocholine or sugar, is attached to the N-acylated sphingoid base (ceramide) forming SM or glycosphingolipid, respectively. Sphingolipids containing VLCFAs have unique cellular functions such as microdomain/raft-mediated signal transduction and cell survival (6Iwabuchi K. Prinetti A. Sonnino S. Mauri L. Kobayashi T. Ishii K. Kaga N. Murayama K. Kurihara H. Nakayama H. et al.Involvement of very long fatty acid-containing lactosylceramide in lactosylceramide-mediated superoxide generation and migration in neutrophils.Glycoconj. J. 2008; 25: 357-374Crossref PubMed Scopus (79) Google Scholar, 7Ohno Y. Suto S. Yamanaka M. Mizutani Y. Mitsutake S. Igarashi Y. Sassa T. Kihara A. ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis.Proc. Natl. Acad. Sci. USA. 2010; 107: 18439-18444Crossref PubMed Scopus (239) Google Scholar, 8Sassa T. Suto S. Okayasu Y. Kihara A. A shift in sphingolipid composition from C24 to C16 increases susceptibility to apoptosis in HeLa cells.Biochim. Biophys. Acta. 2012; 1821: 1031-1037Crossref PubMed Scopus (72) Google Scholar). Ceramides with ≥C26 VLCFAs are also present in the skin and essential for epidermal permeability barrier function (3Vasireddy V. Uchida Y. Salem N. Kim S.Y. Mandal M.N. Reddy G.B. Bodepudi R. Alderson N.L. Brown J.C. Hama H. et al.Loss of functional ELOVL4 depletes very long-chain fatty acids (≥C28) and the unique ω-O-acylceramides in skin leading to neonatal death.Hum. Mol. Genet. 2007; 16: 471-482Crossref PubMed Scopus (202) Google Scholar, 9Jennemann R. Rabionet M. Gorgas K. Epstein S. Dalpke A. Rothermel U. Bayerle A. van der Hoeven F. Imgrund S. Kirsch J. et al.Loss of ceramide synthase 3 causes lethal skin barrier disruption.Hum. Mol. Genet. 2012; 21: 586-608Crossref PubMed Scopus (201) Google Scholar, 10Sassa T. Ohno Y. Suzuki S. Nomura T. Nishioka C. Kashiwagi T. Hirayama T. Akiyama M. Taguchi R. Shimizu H. et al.Impaired epidermal permeability barrier in mice lacking Elovl1, the gene responsible for very-long-chain fatty acid production.Mol. Cell. Biol. 2013; 33: 2787-2796Crossref PubMed Scopus (111) Google Scholar). X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder characterized by progressive demyelination and adrenal insufficiency (11Berger J. Pujol A. 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Berger J. Aubourg P. X-linked adrenoleukodystrophy: clinical, metabolic, genetic and pathophysiological aspects.Biochim. Biophys. Acta. 2012; 1822: 1465-1474Crossref PubMed Scopus (184) Google Scholar). The accumulation of these VLCFAs is believed to play a crucial role in the pathogenesis of X-ALD such as inflammatory demyelination and oxidative damage (18Paintlia A.S. Gilg A.G. Khan M. Singh A.K. Barbosa E. Singh I. Correlation of very long chain fatty acid accumulation and inflammatory disease progression in childhood X-ALD: implications for potential therapies.Neurobiol. Dis. 2003; 14: 425-439Crossref PubMed Scopus (93) Google Scholar, 19Vargas C.R. Wajner M. Sirtori L.R. Goulart L. Chiochetta M. Coelho D. Latini A. Llesuy S. Bello-Klein A. Giugliani R. et al.Evidence that oxidative stress is increased in patients with X-linked adrenoleukodystrophy.Biochim. Biophys. Acta. 2004; 1688: 26-32Crossref PubMed Scopus (94) Google Scholar). Therefore, reducing or preventing the accumulation of VLCFAs by either promoting their degradation or suppressing their synthesis may lead to the treatment of X-ALD. VLCFAs are synthesized by the FA elongation cycle in the endoplasmic reticulum by sequential addition of C2 units from malonyl-CoA to long-chain acyl-CoA (5Kihara A. Very long-chain fatty acids: elongation, physiology and related disorders.J. Biochem. 2012; 152: 387-395Crossref PubMed Scopus (241) Google Scholar, 20Jakobsson A. Westerberg R. Jacobsson A. Fatty acid elongases in mammals: their regulation and roles in metabolism.Prog. Lipid Res. 2006; 45: 237-249Crossref PubMed Scopus (635) Google Scholar). Each elongation cycle is composed of four reactions: condensation, reduction, dehydration, and reduction. The first condensation reaction is the rate-limiting step catalyzed by elongation of very long-chain fatty acid (ELOVL) family proteins. There are seven in (5Kihara A. Very long-chain fatty acids: elongation, physiology and related disorders.J. Biochem. 2012; 152: 387-395Crossref PubMed Scopus (241) Google Scholar, 20Jakobsson A. Westerberg R. Jacobsson A. Fatty acid elongases in mammals: their regulation and roles in metabolism.Prog. Lipid Res. 2006; 45: 237-249Crossref PubMed Scopus (635) Google Scholar), of which for chain length and degree of of the acyl-CoA Y. Suto S. Yamanaka M. Mizutani Y. Mitsutake S. Igarashi Y. Sassa T. Kihara A. ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis.Proc. Natl. Acad. Sci. USA. 2010; 107: 18439-18444Crossref PubMed Scopus (239) Google Scholar). the seven ELOVL1 is highly toward saturated and monounsaturated to Y. Suto S. Yamanaka M. Mizutani Y. Mitsutake S. Igarashi Y. Sassa T. Kihara A. ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis.Proc. Natl. Acad. Sci. USA. 2010; 107: 18439-18444Crossref PubMed Scopus (239) Google Scholar) and is responsible for the synthesis of to such as those in X-ALD. of ELOVL1 in X-ALD is to the level of R. Dijkstra I.M. van Roermund C.W. N. M. van Cruchten A. van Wanders R.J. Kemp S. The role of ELOVL1 in very long-chain fatty acid and X-linked Mol. 2010; PubMed Scopus Google Scholar), ELOVL1 as a potential pharmacological for the treatment of X-ALD S. Berger J. Aubourg P. X-linked adrenoleukodystrophy: clinical, metabolic, genetic and pathophysiological aspects.Biochim. Biophys. Acta. 2012; 1822: 1465-1474Crossref PubMed Scopus (184) Google Scholar, R. Dijkstra I.M. van Roermund C.W. N. M. van Cruchten A. van Wanders R.J. Kemp S. The role of ELOVL1 in very long-chain fatty acid and X-linked Mol. 2010; PubMed Scopus Google Scholar, M. Ofman R. R.J. Dijkstra I.M. S. Pujol A. Poll-The B.T. Wanders R.J. et very long-chain fatty acids in X-linked adrenoleukodystrophy by fatty acid Dis. 2012; PubMed Scopus Google Scholar). Lorenzo's oil, a 4:1 mixture of glyceryl trioleate and glyceryl was in as a treatment for X-ALD patients A. S. R. J.A. erucic acid for X-linked PubMed Google Scholar). the are by in the to and erucic which are from the and and to the tissues where their Lorenzo's oil the of C24:0 and in the plasma of X-ALD patients A. S. R. J.A. erucic acid for X-linked PubMed Google Scholar, P. C. F. N. I. C. A. F. C. et of and erucic acids as treatment for J. 1993; PubMed Scopus Google however, the progression of patients with or adrenal P. C. F. N. I. C. A. F. C. et of and erucic acids as treatment for J. 1993; PubMed Scopus Google Scholar, Moser A.B. K. for X-linked adrenoleukodystrophy: and of Mol. 2007; 33: PubMed Scopus Google Scholar) may have a in patients L.R. Moser A.B. J. P. et of patients with adrenoleukodystrophy with Lorenzo's PubMed Scopus Google Scholar). The of Lorenzo's oil to and erucic acids to the level of in X-ALD D. J. acid saturated fatty PubMed Google Scholar). the mechanism of of Lorenzo's oil has the of and erucic acids to their by inhibition of inhibition of VLCFA synthesis by and erucic acids of saturated VLCFAs by and erucic acids their and of lipid by and erucic by of various cellular and gene M. of gene regulation by fatty Lipid Res. 2012; 51: PubMed Scopus Google Scholar). In the present characterized the activity of Lorenzo's oil toward ELOVL1 in and cellular FA elongation to Lorenzo's oil saturated VLCFAs. HeLa and in for HeLa and for containing and with and in with to the the and the Y. Suto S. Yamanaka M. Mizutani Y. Mitsutake S. Igarashi Y. Sassa T. Kihara A. ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis.Proc. Natl. Acad. Sci. USA. 2010; 107: 18439-18444Crossref PubMed Scopus (239) Google Scholar). The was by the with and HeLa with the to with at the the level of protein and was used for the The was the as Y. Suto S. Yamanaka M. Mizutani Y. Mitsutake S. Igarashi Y. Sassa T. Kihara A. ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis.Proc. Natl. Acad. Sci. USA. 2010; 107: 18439-18444Crossref PubMed Scopus (239) Google Scholar). the was with and in reaction 2 at for The of erucic and their as as and from on ELOVL1 activity was by FA in 2 or the of in the The reaction was by and by at for and the mixture was with in with and The lipid was in 20 and by on a with acid as the lipids by and by a The used the acid and and acids and and acids The latter two in by of and which in synthesized from and with the of Y. Suto S. Yamanaka M. Mizutani Y. Mitsutake S. Igarashi Y. Sassa T. Kihara A. ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis.Proc. Natl. Acad. Sci. USA. 2010; 107: 18439-18444Crossref PubMed Scopus (239) Google Scholar). HeLa in with in in at for of with containing from the a cell and in from the by addition and of and at and for the was and The lipid was in and by on a with as the lipids and by a the of the chain length of the the lipids from the to and the FA and a as Y. Suto S. Yamanaka M. Mizutani Y. Mitsutake S. Igarashi Y. Sassa T. Kihara A. ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis.Proc. Natl. Acad. Sci. USA. 2010; 107: 18439-18444Crossref PubMed Scopus (239) Google Scholar). was as Y. Suto S. Yamanaka M. Mizutani Y. Mitsutake S. Igarashi Y. Sassa T. Kihara A. ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis.Proc. Natl. Acad. Sci. USA. 2010; 107: 18439-18444Crossref PubMed Scopus (239) Google Scholar) the as the primary and as the The signal was with with an and in at and for the was and with in at for by with addition of the was and and the lipid was in SM was by by on a length and the was by in the with a of The by the seven ELOVL1 is responsible for the synthesis of to Y. Suto S. Yamanaka M. Mizutani Y. Mitsutake S. Igarashi Y. Sassa T. Kihara A. ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis.Proc. Natl. Acad. Sci. USA. 2010; 107: 18439-18444Crossref PubMed Scopus (239) Google Scholar). We HeLa or ELOVL1 their increased ELOVL1 also HeLa either or ELOVL1 in which the for family for was with The is to be in the and its mutations in the and in in the of their V. A mechanism for very long-chain fatty acid 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, T. Y. Sassa T. Ohno Y. Kihara A. characterization of the very long-chain fatty acid 2011; PubMed Scopus (73) Google Scholar). the and the at a level The from these and for their ELOVL1 in the in FA elongation with as the C2 and as the The reaction by to the FAs the from those HeLa ELOVL1, from the increased ELOVL1 activity as with the Therefore, the from HeLa ELOVL1 was used in the FA elongation where in which the from ELOVL1 Y. Suto S. Yamanaka M. Mizutani Y. Mitsutake S. Igarashi Y. Sassa T. Kihara A. ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis.Proc. Natl. Acad. Sci. USA. 2010; 107: 18439-18444Crossref PubMed Scopus (239) Google Scholar) was We first the of FAs with chain length and degree of on ELOVL1 activity. the in FA elongation was in the of acid a major of Lorenzo's or Oleic acid was to ELOVL1 activity in a with inhibition at 20 whereas exhibited inhibition at 20 The saturated of acid on ELOVL1 activity at The saturated acid and acid be due to their in the Lorenzo's oil is a 4:1 mixture of and erucic the in FA elongation was in the of a mixture in of and erucic acids and The of the mixture was at 20 which is the at which acid inhibitory activity. acid to ELOVL1 activity at 20 the was of and erucic acids inhibitory activity to or that of with the 4:1 mixture (the FA of Lorenzo's oil) the most the of a 4:1 mixture of and erucic acids oil) as a potent of ELOVL1, a characterization of this inhibition mechanism of inhibition was that and erucic acids with the for the of ELOVL1 this is the the inhibition be by the The in FA elongation was at various of in the or of a 4:1 mixture of and erucic acids at a of 20 In the of the 4:1 ELOVL1 activity a at a of and The of may have a on ELOVL1, which is to be to by T. Y. Sassa T. Ohno Y. Kihara A. characterization of the very long-chain fatty acid 2011; PubMed Scopus (73) Google Scholar). In the of the 4:1 inhibition of ELOVL1 at that the mechanism of inhibition is We these by a to the and of ELOVL1 toward at the of used the at 1, and 3 a of the ELOVL1 activity The and of ELOVL1 for to be and and those in the of the 4:1 mixture and respectively. The and also to be and respectively. These suggest that ELOVL1 inhibition by a 4:1 mixture of and erucic acids oil) is a mixed inhibition in which these acids to the We the of and erucic acids HeLa The with and erucic as as with and acids for to and of acid was by and to and and to a to sphingolipids and In of which was by was to and acids by and to be to The chain length of the was by of these lipids by analysis of of acid was to acid whereas the of mostly The elongation of erucic to acids is catalyzed by ELOVL1 Y. Suto S. Yamanaka M. Mizutani Y. Mitsutake S. Igarashi Y. Sassa T. Kihara A. ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis.Proc. Natl. Acad. Sci. USA. 2010; 107: 18439-18444Crossref PubMed Scopus (239) Google Scholar). in saturated and monounsaturated VLCFAs are into sphingolipids, that the inhibition of ELOVL1 responsible for VLCFA synthesis a sphingolipid the of the most abundant of with a 4:1 mixture of and erucic acids for with the of We used these FAs in the of as their (the composition of Lorenzo's oil) most are first to acids and by to two of containing and and the containing VLCFAs and was in HeLa with the 4:1 mixture reduced the level of saturated and at and saturated at 20 This is with the results in X-ALD by et D. J. acid saturated fatty PubMed Google Scholar). with the of and monounsaturated was increased At 20 a was also for a the of monounsaturated to saturated at 20 of the 4:1 mixture with the In treatment with either or acid at 20 on the SM for a increased level of saturated SM and or and This is with the that acid ELOVL1 activity and that and acids are to to sphingolipids We also the ELOVL1 level by in HeLa with a 4:1 mixture of and erucic acids for and caused by the treatment The results suggest that Lorenzo's oil the synthesis of saturated VLCFAs by ELOVL1 at the protein level at the has been two Lorenzo's oil was to the level in X-ALD and plasma A. S. R. J.A. erucic acid for X-linked PubMed Google Scholar, P. C. F. N. I. C. A. F. C. et of and erucic acids as treatment for J. 1993; PubMed Scopus Google Scholar, D. J. acid saturated fatty PubMed Google however, Lorenzo's oil exerts such has The results of present for the first the Lorenzo's oil and the of the saturated VLCFA We that a 4:1 mixture of and erucic acids the activity of ELOVL1 by a mixed inhibition by inhibition however, at present remains these with We that the family are (5Kihara A. Very long-chain fatty acids: elongation, physiology and related disorders.J. Biochem. 2012; 152: 387-395Crossref PubMed Scopus (241) Google Scholar, 20Jakobsson A. Westerberg R. Jacobsson A. Fatty acid elongases in mammals: their regulation and roles in metabolism.Prog. Lipid Res. 2006; 45: 237-249Crossref PubMed Scopus (635) Google Scholar), and erucic acids may with ELOVL1 by the of ELOVL1, preventing the for its activity. This may also that monounsaturated and erucic and inhibited ELOVL1 activity in the FA chain its and due to the of the and such Lorenzo's oil to have the of and erucic acids for ELOVL1 inhibition. We also that with a 4:1 mixture of and erucic acids a reduced level of SM with either saturated or as a of the inhibition of ELOVL1 regulation of the ELOVL1 gene In the the of and was accompanied by an in the level of This probably results from the of of the and erucic acids to the acyl-CoAs and by their incorporation into the FA elongation cycle by either the ELOVL1 activity or that acid was to acid and into sphingolipids, the elongation of acid was The incorporation of to sphingolipids to be with the that saturated and monounsaturated VLCFAs are in sphingolipids T. Ohno Y. Suzuki S. Nomura T. Nishioka C. Kashiwagi T. Hirayama T. Akiyama M. Taguchi R. Shimizu H. et al.Impaired epidermal permeability barrier in mice lacking Elovl1, the gene responsible for very-long-chain fatty acid production.Mol. Cell. Biol. 2013; 33: 2787-2796Crossref PubMed Scopus (111) Google Scholar, Y. H. S. J. R. T. F. et role for ceramide synthase 2 in I. in lipid Biol. Chem. 2010; Full Text Full Text PDF PubMed Scopus (179) Google Scholar). This may the increased of monounsaturated VLCFAs and in the plasma of patients with Lorenzo's oil A. S. R. J.A. erucic acid for X-linked PubMed Google Scholar). the a that the increased with the saturated acyl-CoAs for the ELOVL1 to the of saturated VLCFA however, such a is for acid is a for ELOVL1 Y. Suto S. Yamanaka M. Mizutani Y. Mitsutake S. Igarashi Y. Sassa T. Kihara A. ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis.Proc. Natl. Acad. Sci. USA. 2010; 107: 18439-18444Crossref PubMed Scopus (239) Google Scholar). Lorenzo's oil may the C24:0 and by a of two ELOVL1 inhibition by and erucic acids and ELOVL1 inhibition by to that the of Lorenzo's oil is at in a of its ELOVL1 inhibition. Although Lorenzo's oil plasma C24:0 and in X-ALD or their A. S. R. J.A. erucic acid for X-linked PubMed Google Scholar, P. C. F. N. I. C. A. F. C. et of and erucic acids as treatment for J. 1993; PubMed Scopus Google Scholar). the treatment increases their plasma and A. S. R. J.A. erucic acid for X-linked PubMed Google Scholar), the of which on the of X-ALD is is to the of X-ALD and to The are to T. for of the with elongation of very long-chain fatty acid long-chain fatty acid very long-chain fatty acid X-linked adrenoleukodystrophy