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

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 Δfaa1 Δfaa4 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.

Sphingolipid Homeostasis in the Endoplasmic Reticulum and Beyond

“…This reaction represents the only mechanism for the irreversible degradation of sphingolipids, and thus lyase activity is likely to be tightly regulated (Fyrst and Saba 2008). The ER enzymes that convert lyase-generated acyl aldehydes back into FA-CoAs for use in sphingolipid or glycerolipid synthesis have recently been identified, thus revealing the final steps of the sphingolipid metabolic pathway (Nakahara et al 2012). …”

Mouse aldehyde dehydrogenase ALDH3B2 is localized to lipid droplets via two C-terminal tryptophan residues and lipid modification

“…For example, in the metabolic pathway of the lipid mediator S1P, S1P is cleaved to the fatty aldehyde hexadecenal and phosphoethanolamine [14]. Hexadecenal is oxidized to hexadecenoic acid by ALDH3A2 and is further metabolized to glycerophospholipids [13]. ALDH3A2 is the causative gene of the neurocutaneous disorder Sjögren-Larsson syndrome [2], whose pathology is believed to be caused by the accumulation of lipid-derived aldehydes, including hexadecenal [12][13][14].…”

“…Hexadecenal is oxidized to hexadecenoic acid by ALDH3A2 and is further metabolized to glycerophospholipids [13]. ALDH3A2 is the causative gene of the neurocutaneous disorder Sjögren-Larsson syndrome [2], whose pathology is believed to be caused by the accumulation of lipid-derived aldehydes, including hexadecenal [12][13][14]. Oxidative stress generates free radicals that react with unsaturated fatty acids, and the resulting lipid hydroperoxides are degraded into several compounds, such as 4-HNE from n-6 polyunsaturated fatty acids [35].…”

“…For example, the dominant splicing isoform of ALDH3A2 is localized to the ER, which is a major site of lipid metabolism. S1P metabolism also occurs in the ER and the ER-resident ALDH3A2 oxidizes the S1P metabolite hexadecenal [13].…”

“…The major splicing isoform of ALDH3A2 is a type II endoplasmic reticulum (ER) membrane protein, whereas its minor isoform is localized to peroxisomes [10,11]. A variety of ALDH3A2 substrates are generated through the metabolism of lipids such as fatty alcohols, leukotriene B 4 , phytol, and sphingosine-1-phosphate (S1P) and through lipid peroxidation [12][13][14].…”