Lorenzo's oil inhibits ELOVL1 and lowers the level of sphingomyelin with a saturated very long-chain fatty acid.
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.
Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo 060-0812, Japan.
Takayuki
T
Sassa
Takeshi
T
Wakashima
Yusuke
Y
Ohno
Akio
A
Kihara
D000123:Acetyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004883:Erucic Acids / Q000494:pharmacology*; D000081031:Fatty Acid Elongases; D005227:Fatty Acids / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D007700:Kinetics; D019301:Oleic Acid / Q000494:pharmacology; D019308:Palmitic Acid / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013109:Sphingomyelins / Q000378:metabolism*; D013229:Stearic Acids / Q000494:pharmacology; D014304:Triolein / Q000494:pharmacology*
D004338:Drug Combinations; C000630949:ELOVL1 protein, human; D004883:Erucic Acids; D005227:Fatty Acids; C079420:Lorenzo's oil; D013109:Sphingomyelins; D013229:Stearic Acids; D014304:Triolein; D019301:Oleic Acid; D019308:Palmitic Acid; C031183:stearic acid; D000123:Acetyltransferases; D000081031:Fatty Acid Elongases
ABCD1; X-linked adrenoleukodystrophy; elongation of very long-chain fatty acid 1; erucic acid; oleic acid; peroxisome; sphingolipids