Microsomal fatty aldehyde dehydrogenase catalyzes the oxidation of aliphatic aldehyde derived from ether glycerolipid catabolism: implications for Sjögren–Larsson syndrome

Abstract

The enzyme that catalyzes the oxidation of fatty aldehyde derived from ether glycerolipid catabolism has not been identified. To determine whether microsomal fatty aldehyde dehydrogenase (FALDH) is responsible, we investigated the metabolism of 1-O-[9, 10-(3)H-octadecyl]-glycerol ([(3)H]OG) in FALDH-deficient cultured cells from patients with Sjögren-Larsson syndrome (SLS) and in mutant Chinese hamster ovary (CHO) cells. Intact fibroblasts from SLS patients incubated with [(3)H]OG showed a selective deficiency (38+/-7% of normal) in the incorporation of radioactivity into fatty acid, but no decrease in incorporation of radioactivity into fatty alcohol, total lipids and phosphatidylethanolamine (PE). Consistent with fatty aldehyde accumulation, incorporation of radioactivity into N-alkyl-phosphatidylethanolamine, which is derived from Schiff base formation of free aldehyde with PE, was 4-fold higher in SLS fibroblasts compared to normal controls. Similar results were seen with SLS keratinocytes, whereas FALDH-deficient CHO cells showed a more profound reduction in radioactive fatty acid to 12+/-2% of normal. These results implicate FALDH in the oxidation of ether-derived fatty aldehyde in human and rodent cells. Metabolism of ether glycerolipids is a previously unrecognized source of fatty aldehyde that may contribute to the pathogenesis of SLS.

Chlorinated lipid species in activated human neutrophils: lipid metabolites of 2-chlorohexadecanal

“…It was determined that less 2-ClHA was produced and released from the FAA.K1A cell line in comparison to the control CHO.K1 cell line. In addition to cellular fatty alcohol accumulation, fatty alcohol is present in the plasma of SLS and autosomal recessive form of rhizomelic chondrodysplasia punctata patients and can act as a biomarker of enzymatic defects (29)(30)(31). Likewise, 2-ClHDA metabolism to 2-ClHOH was also signifi cantly increased in the FAA.K1A cells in comparison to the control CHO.K1 cell line.…”

“…Patients affected by disorders of fatty alcohol metabolism such as Sjogren-Larson syndrome (SLS) or the autosomal recessive form of rhizomelic chondrodysplasia punctata have increased cellular fatty alcohol accumulation due to the inability to either oxidize the fatty alcohol or to incorporate the alcohol in ether-linked lipids such as plasmalogens, respectively (29)(30)(31). The metabolism of 2-ClHDA to 2-ClHA and 2-ClHOH was analyzed using a FALDH-defective cell line.…”

Sjögren–Larsson syndrome: Molecular genetics and biochemical pathogenesis of fatty aldehyde dehydrogenase deficiency

“…Cultured fibroblasts and keratinocytes from SLS patients carry out the cleavage step normally, but have an impaired ability to oxidize the fatty aldehyde to fatty acid [47].…”

“…MR spectroscopy of the abnormal white matter of SLS patients reveals one or two unusual lipid peaks with a spectrum that resembles fatty alcohol or other aliphatic lipids [15,72]. It is possible that turnover of plasmalogen lipids, which are particularly abundant in myelin, generates fatty aldehydes that are poorly oxidized in SLS [47] and diverted into fatty alcohols or form adducts with phosphatidy lethanolamine and myelin proteins.…”

Abnormal fatty alcohol metabolism in cultured keratinocytes from patients with Sjögren-Larsson syndrome

“…Owing to FAO deficiency, patients with SLS accumulate long-chain fatty alcohols in cultured fibroblasts and plasma (6). In addition, fibroblasts from SLS patients have deficient metabolism of fatty aldehydes generated from the catabolism of ether glycerolipids (7). In vitro studies with SLS fibroblasts implicate FALDH in the conversion of phytol, a branched-chain fatty alcohol derived from the diet, to phytanic acid (8) and in the subsequent a-oxidation of phytanic acid that generates a fatty aldehyde product (9).…”