Studying fatty aldehyde metabolism in living cells with pyrene-labeled compounds

Keller, Markus A.; Watschinger, Katrin; Lange, Karsten; Golderer, Georg; Werner-Felmayer, Gabriele; Hermetter, Albin; Wanders, Ronald J. A.; Werner, Ernst R.

doi:10.1194/jlr.d025650

Cited by 16 publications

(22 citation statements)

References 22 publications

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“…However, there is no accumulation of fatty aldehydes in serum or fibroblasts of SLS patients (Rizzo 1998). This puzzling observation is explained by the apparent conversion of fatty aldehydes to their corresponding fatty alcohols, as shown in fibroblasts from SLS patients (Keller et al 2012). Additionally, the high instability and reactivity of fatty aldehydes that readily form Schiff bases with amino groups of lipids and proteins may render their detection more difficult (James and Zoeller 1997).…”

Section: Sjögren-larsson Syndromementioning

confidence: 90%

Plasmalogens and fatty alcohols in rhizomelic chondrodysplasia punctata and Sjögren‐Larsson syndrome

Malheiro¹,

Silva²,

Brites³

2014

J of Inher Metab Disea

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Plasmalogens are a special class of ether-phospholipids, best recognized by their vinyl-ether bond at the sn-1 position of the glycerobackbone and by the observation that their deficiency causes rhizomelic chondrodysplasia punctata (RCDP). The complex plasmalogen biosynthetic pathway involves multiple enzymatic steps carried-out in peroxisomes and in the endoplasmic reticulum. The rate limiting step in the biosynthesis of plasmalogens resides in the formation of the fatty alcohol responsible for the formation of an intermediate with an alkyl-linked moiety. The regulation in the biosynthesis of plasmalogens also takes place at this step using a feedback mechanism to stimulate or inhibit the biosynthesis. As such, fatty alcohols play a relevant role in the formation of ether-phospholipids. These advances in our understanding of complex lipid biosynthesis brought two seemingly distinct disorders into the spotlight. Sjögren-Larsson syndrome (SLS) is caused by defects in the microsomal fatty aldehyde dehydrogenase (FALDH) leading to the accumulation of fatty alcohols and fatty aldehydes. In RCDP cells, the defect in plasmalogens is thought to generate a feedback signal to increase their biosynthesis, through the activity of fatty acid reductases to produce fatty alcohols. However, the enzymatic defects in either glyceronephosphate O-acyltransferase (GNPAT) or alkylglycerone phosphate synthase (AGPS) disrupt the biosynthesis and result in the accumulation of the fatty alcohols. A detailed characterization on the processes and enzymes that govern these intricate biosynthetic pathways, as well as, the metabolic characterization of defects along the pathway should increase our understanding of the causes and mechanisms behind these disorders.

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Section: Sjögren-larsson Syndromementioning

confidence: 90%

Plasmalogens and fatty alcohols in rhizomelic chondrodysplasia punctata and Sjögren‐Larsson syndrome

Malheiro¹,

Silva²,

Brites³

2014

J of Inher Metab Disea

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“…FALDH-deficient hamster cells and SLS fibroblasts [123] and keratinocytes [124] are more susceptible to these aldehydes than normal cells, although this conclusion for fibroblasts is unconfirmed [125]. It is thought that cytotoxicity originates from the propensity of aldehydes to form covalent adducts with other molecules [37,126].…”

Section: Biochemical Pathogenesis Of Epidermal Dysfunction In Slsmentioning

confidence: 99%

“…These long-chain alcohols are expected to partition into cellular membranes rather than exist free in solution [129, 130] and could thereby alter membrane structure and function through their detergent effects. Cultured SLS fibroblasts are reported to be more sensitive to cytotoxic effects of hexadecanol than control cells [125]. However, feeding studies in rodents have revealed no harmful effects of octadecanol, even with high levels of dietary intake (Rizzo, unpublished observations).…”

Section: Biochemical Pathogenesis Of Epidermal Dysfunction In Slsmentioning

confidence: 99%

Fatty aldehyde and fatty alcohol metabolism: Review and importance for epidermal structure and function

Rizzo

2014

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

101

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Normal fatty aldehyde and alcohol metabolism is essential for epidermal differentiation and function. Long-chain aldehydes are produced by catabolism of several lipids including fatty alcohols, sphingolipids, ether glycerolipids, isoprenoid alcohols and certain aliphatic lipids that undergo α- or ω-oxidation. The fatty aldehyde generated by these pathways is chiefly metabolized to fatty acid by fatty aldehyde dehydrogenase (FALDH, alternately known as ALDH3A2), which also functions to oxidize fatty alcohols as a component of the fatty alcohol:NAD oxidoreductase (FAO) enzyme complex. Genetic deficiency of FALDH/FAO in patients with Sjögren-Larsson syndrome (SLS) results in accumulation of fatty aldehydes, fatty alcohols and related lipids (ether glycerolipids, wax esters) in cultured keratinocytes. These biochemical changes are associated with abnormalities in formation of lamellar bodies in the stratum granulosum and impaired delivery of their precursor membranes to the stratum corneum (SC). The defective extracellular SC membranes are responsible for a leaky epidermal water barrier and ichthyosis. Although lamellar bodies appear to be the pathogenic target for abnormal fatty aldehyde/alcohol metabolism in SLS, the precise biochemical mechanisms are yet to be elucidated. Nevertheless, studies in SLS highlight the critical importance of FALDH and normal fatty aldehyde/alcohol metabolism for epidermal function.

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“…AGMO activity in homogenates was analyzed using a fluorescent alkylglycerol by HPLC (30). AGMO activity in live cells was measured by feeding a fluorescent alkylglycerol, collecting supernatants, and analyzing the fluorescent acid product released from the cells (14). GCH1 activity was analyzed according to ref.…”

Section: Methodsmentioning

confidence: 99%

Tetrahydrobiopterin and alkylglycerol monooxygenase substantially alter the murine macrophage lipidome

Watschinger

Keller

McNeill

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Tetrahydrobiopterin is a cofactor synthesized from GTP with well-known roles in enzymatic nitric oxide synthesis and aromatic amino acid hydroxylation. It is used to treat mild forms of phenylketonuria. Less is known about the role of tetrahydrobiopterin in lipid metabolism, although it is essential for irreversible ether lipid cleavage by alkylglycerol monooxygenase. Here we found intracellular alkylglycerol monooxygenase activity to be an important regulator of alkylglycerol metabolism in intact murine RAW264.7 macrophage-like cells. Alkylglycerol monooxygenase was expressed and active also in primary mouse bone marrowderived monocytes and "alternatively activated" M2 macrophages obtained by interleukin 4 treatment, but almost missing in M1 macrophages obtained by IFN-γ and lipopolysaccharide treatment. The cellular lipidome of RAW264.7 was markedly changed in a parallel way by modulation of alkylglycerol monooxygenase expression and of tetrahydrobiopterin biosynthesis affecting not only various ether lipid species upstream of alkylglycerol monooxygenase but also other more complex lipids including glycosylated ceramides and cardiolipins, which have no direct connection to ether lipid pathways. Alkylglycerol monooxygenase activity manipulation modulated the IFN-γ/lipopolysaccharide-induced expression of inducible nitric oxide synthase, interleukin-1β, and interleukin 1 receptor antagonist but not transforming growth factor β1, suggesting that alkylglycerol monooxygenase activity affects IFN-γ/lipopolysaccharide signaling. Our results demonstrate a central role of tetrahydrobiopterin and alkylglycerol monooxygenase in ether lipid metabolism of murine macrophages and reveal that alteration of alkylglycerol monooxygenase activity has a profound impact on the lipidome also beyond the class of ether lipids. alkylglycerols | lipidomics | macrophages | RAW264.7 | tetrahydrobiopterin

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Studying fatty aldehyde metabolism in living cells with pyrene-labeled compounds

Cited by 16 publications

References 22 publications

Plasmalogens and fatty alcohols in rhizomelic chondrodysplasia punctata and Sjögren‐Larsson syndrome

Plasmalogens and fatty alcohols in rhizomelic chondrodysplasia punctata and Sjögren‐Larsson syndrome

Fatty aldehyde and fatty alcohol metabolism: Review and importance for epidermal structure and function

Tetrahydrobiopterin and alkylglycerol monooxygenase substantially alter the murine macrophage lipidome

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