A mammalian fatty acid hydroxylase responsible for the formation of α-hydroxylated galactosylceramide in myelin

Eckhardt, Matthias; Yaghootfam, Afshin; Fewou, Simon Ngamli; Zöller, Inge; Gieselmann, Volkmar

doi:10.1042/bj20041451

Cited by 117 publications

(97 citation statements)

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“…In line with this, the only known enzyme catalyzing the 2-hydroxylation of unbranched fatty acids, fatty acid 2-hydroxylase (FA2H) (12)(13)(14), is highly expressed in murine skin (13). Furthermore, differentiation-dependent up-regulation of Fa2h has been observed in human keratinocytes (15), suggesting that FA2H is responsible for synthesis of 2-hydroxylated sphingolipids in keratinocytes of mammalian skin.…”

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confidence: 69%

“…In Situ Hybridization-Digoxigenin-labeled cRNA probes were transcribed from FA2H cDNA as described previously (13). Hybridization of digoxigenin-labeled cRNA probes to skin paraffin sections was done as described previously (18).…”

Section: Methodsmentioning

confidence: 99%

“…Mice-Fa2h is strongly expressed in murine skin (13), and its expression exhibits hair cycle-dependent changes in wildtype mice (Fig. 1A).…”

Section: Delayed Fur Emergence and Cyclic Alopecia In Fa2h-deficientmentioning

confidence: 99%

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Normal Fur Development and Sebum Production Depends on Fatty Acid 2-Hydroxylase Expression in Sebaceous Glands

Maier

Meixner

Hartmann

et al. 2011

Journal of Biological Chemistry

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2-Hydroxylated fatty acid (HFA)-containing sphingolipids are abundant in mammalian skin and are believed to play a role in the formation of the epidermal barrier. Fatty acid 2-hydroxylase (FA2H), required for the synthesis of 2-hydroxylated sphingolipids in various organs, is highly expressed in skin, and previous in vitro studies demonstrated its role in the synthesis of HFA sphingolipids in human keratinocytes. Unexpectedly, however, mice deficient in FA2H did not show significant changes in their epidermal HFA sphingolipids. Expression of FA2H in murine skin was restricted to the sebaceous glands, where it was required for synthesis of 2-hydroxylated glucosylceramide and a fraction of type II wax diesters. Absence of FA2H resulted in hyperproliferation of sebocytes and enlarged sebaceous glands during hair follicle morphogenesis and anagen (active growth phase) in adult mice. This was accompanied by a significant up-regulation of the epidermal growth factor receptor ligand epigen in sebocytes. Loss of FA2H significantly altered the composition and physicochemical properties of sebum, which often blocked the hair canal, apparently causing a delay in the hair fiber exit. Furthermore, mice lacking FA2H displayed a cycling alopecia with hair loss in telogen. These results underline the importance of the sebaceous glands and suggest a role of specific sebaceous gland or sebum lipids, synthesized by FA2H, in the hair follicle homeostasis.

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confidence: 69%

Section: Methodsmentioning

confidence: 99%

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Normal Fur Development and Sebum Production Depends on Fatty Acid 2-Hydroxylase Expression in Sebaceous Glands

Maier

Meixner

Hartmann

et al. 2011

Journal of Biological Chemistry

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“…Fatty acid 2-hydroxylase (FA2H) was recently identified as an enzyme involved in the synthesis of 2-hydroxylated sphingolipids (Alderson et al, 2004;Eckhardt et al, 2005). To prove the hypothesis that FA2H synthesizes HFAsphingolipids in myelinating glial cells and to examine a possible role of HFAsphingolipids in myelin formation and function, we generated mice deficient in FA2H (FA2H Ϫ/Ϫ ).…”

Section: Introductionmentioning

confidence: 99%

Absence of 2-Hydroxylated Sphingolipids Is Compatible with Normal Neural Development But Causes Late-Onset Axon and Myelin Sheath Degeneration

Zöller¹,

Meixner²,

Hartmann³

et al. 2008

J. Neurosci.

159

134

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Sphingolipids containing 2-hydroxylated fatty acids are among the most abundant lipid components of the myelin sheath and therefore are thought to play an important role in formation and function of myelin. To prove this hypothesis, we generated mice lacking a functional fatty acid 2-hydroxylase (FA2H) gene. FA2H-deficient (FA2H Ϫ/Ϫ ) mice lacked 2-hydroxylated sphingolipids in the brain and in peripheral nerves. In contrast, nonhydroxylated galactosylceramide was increased in FA2H Ϫ/Ϫ mice. However, oligodendrocyte differentiation examined by in situ hybridization with cRNA probes for proteolipid protein and PDGF␣ receptor and the time course of myelin formation were not altered in FA2H Ϫ/Ϫ mice compared with wild-type littermates. Nerve conduction velocity measurements of sciatic nerves revealed no significant differences between FA2H Ϫ/Ϫ and wild-type mice. Moreover, myelin of FA2H Ϫ/Ϫ mice up to 5 months of age appeared normal at the ultrastructural level, in the CNS and peripheral nervous system. Myelin thickness and g-ratios were normal in FA2H Ϫ/Ϫ mice. Aged (18-month-old) FA2H Ϫ/Ϫ mice, however, exhibited scattered axonal and myelin sheath degeneration in the spinal cord and an even more pronounced loss of stainability of myelin sheaths in sciatic nerves. These results show that structurally and functionally normal myelin can be formed in the absence of 2-hydroxylated sphingolipids but that its long-term maintenance is strikingly impaired. Because axon degeneration appear to start rather early with respect to myelin degenerations, these lipids might be required for glial support of axon function.

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“…The FA 2-hydroxylase FA2H directly forms 2-OH FAs from FAs (12,17). Although the PHS degradation pathway generates 2-OH C16:0-COOH almost exclusively, FA2H can produces 2-OH FAs ranging from long chain to very long chain (17,41). 2-OH very long-chain FAs with C22 or C24 chain length exist abundantly in galactosylceramides and sulfatides in myelin and are important for myelin function and maintenance (16,(18)(19)(20).…”

Section: Discussionmentioning

confidence: 99%

Phytosphingosine degradation pathway includes fatty acid α-oxidation reactions in the endoplasmic reticulum

Kitamura

Seki

Kihara

2017

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

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Although normal fatty acids (FAs) are degraded via β-oxidation, unusual FAs such as 2-hydroxy (2-OH) FAs and 3-methyl-branched FAs are degraded via α-oxidation. Phytosphingosine (PHS) is one of the long-chain bases (the sphingolipid components) and exists in specific tissues, including the epidermis and small intestine in mammals. In the degradation pathway, PHS is converted to 2-OH palmitic acid and then to pentadecanoic acid (C15:0-COOH) via FA α-oxidation. However, the detailed reactions and genes involved in the α-oxidation reactions of the PHS degradation pathway have yet to be determined. In the present study, we reveal the entire PHS degradation pathway: PHS is converted to C15:0-COOH via six reactions [phosphorylation, cleavage, oxidation, CoA addition, cleavage (C1 removal), and oxidation], in which the last three reactions correspond to the α-oxidation. The aldehyde dehydrogenase ALDH3A2 catalyzes both the first and second oxidation reactions (fatty aldehydes to FAs). In Aldh3a2-deficient cells, the unmetabolized fatty aldehydes are reduced to fatty alcohols and are incorporated into ether-linked glycerolipids. We also identify HACL2 (2-hydroxyacyl-CoA lyase 2) [previous name, ILVBL; ilvB (bacterial acetolactate synthase)-like] as the major 2-OH acyl-CoA lyase involved in the cleavage (C1 removal) reaction in the FA α-oxidation of the PHS degradation pathway. HACL2 is localized in the endoplasmic reticulum. Thus, in addition to the already-known FA α-oxidation in the peroxisomes, we have revealed the existence of FA α-oxidation in the endoplasmic reticulum in mammals.α-oxidation | fatty acid | metabolism | lipid | sphingolipid M ost cellular fatty acids (FAs) have a nonhydroxylated straight chain and are degraded via β-oxidation either in the mitochondria for long-chain FAs (C11-C20), or in the peroxisomes for very long-chain FAs (≥C21) (1, 2). However, unusual FAs, such as 2-hydroxy (2-OH) FAs and 3-methyl-branched FAs (i.e., food-derived phytanic acid), are degraded via α-oxidation (2-4). During FA synthesis by FA synthase type I, acetyl-acyl carrier proteins (ACPs) receive two-carbon units from malonyl-ACP seven times to produce palmitoyl-ACP, followed by thioester bond cleavage to release palmitic acid (C16:0-COOH) (5). Some of the cellular FAs are further elongated via the FA elongation cycle in the endoplasmic reticulum (ER). In each cycle, the FA chain length is elongated by two (6, 7). In the FA degradation pathway (β-oxidation), the FA chain length is shortened by two as acetylCoA is released (1). Thus, all FA synthesis, elongation, and degradation steps proceed by two-carbon units. Accordingly, most cellular FAs are even-numbered. However, odd-numbered FAs also exist, albeit at much lower levels, because α-oxidation produces odd-numbered FAs from 2-OH FAs (8, 9).Sphingolipids are one of the major lipid classes in eukaryotes. The sphingolipid backbone ceramide (CER) is composed of a longchain base (LCB) and an FA (10, 11). Although the FA moiety of CERs is nonhydroxylated in most tissues, CERs...

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A mammalian fatty acid hydroxylase responsible for the formation of α-hydroxylated galactosylceramide in myelin

Cited by 117 publications

References 50 publications

Normal Fur Development and Sebum Production Depends on Fatty Acid 2-Hydroxylase Expression in Sebaceous Glands

Normal Fur Development and Sebum Production Depends on Fatty Acid 2-Hydroxylase Expression in Sebaceous Glands

Absence of 2-Hydroxylated Sphingolipids Is Compatible with Normal Neural Development But Causes Late-Onset Axon and Myelin Sheath Degeneration

Phytosphingosine degradation pathway includes fatty acid α-oxidation reactions in the endoplasmic reticulum

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