The Sjögren-Larsson Syndrome Gene Encodes a Hexadecenal Dehydrogenase of the Sphingosine 1-Phosphate Degradation Pathway

Kanae Nakahara, Aya Ohkuni, Takuya Kitamura, Kensuke Abe, Tatsuro Naganuma, Yusuke Ohno, Raphael A. Zoeller, Akio Kihara

Research output: Contribution to journalArticle

87 Citations (Scopus)

Abstract

Sphingosine 1-phosphate (S1P) functions not only as a bioactive lipid molecule, but also as an important intermediate of the sole sphingolipid-to-glycerolipid metabolic pathway. However, the precise reactions and the enzymes involved in this pathway remain unresolved. We report here that yeast HFD1 and the Sjögren-Larsson syndrome (SLS)-causative mammalian gene ALDH3A2 are responsible for conversion of the S1P degradation product hexadecenal to hexadecenoic acid. The absence of ALDH3A2 in CHO-K1 mutant cells caused abnormal metabolism of S1P/hexadecenal to ether-linked glycerolipids. Moreover, we demonstrate that yeast Faa1 and Faa4 and mammalian ACSL family members are acyl-CoA synthetases involved in the sphingolipid-to-glycerolipid metabolic pathway and that hexadecenoic acid accumulates in Δ faa1 Δ faa4 mutant cells. These results unveil the entire S1P metabolic pathway: S1P is metabolized to glycerolipids via hexadecenal, hexadecenoic acid, hexadecenoyl-CoA, and palmitoyl-CoA. From our results we propose a possibility that accumulation of the S1P metabolite hexadecenal contributes to the pathogenesis of SLS.

Original languageEnglish
Pages (from-to)461-471
Number of pages11
JournalMolecular Cell
Volume46
Issue number4
DOIs
Publication statusPublished - 2012 May 25
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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