Impaired Epidermal Permeability Barrier in Mice Lacking <i>Elovl1</i>, the Gene Responsible for Very-Long-Chain Fatty Acid Production

Sassa, Takayuki; Ohno, Yusuke; Suzuki, Shotaro; Nomura, Toshifumi; Nishioka, Chieko; Kashiwagi, Toshiki; Hirayama, T; Akiyama, Masashi; Taguchi, Ryo; Shimizu, Hiroshi; Itohara, Shigeyoshi; Kihara, Akio

doi:10.1128/mcb.00192-13

Cited by 143 publications

(172 citation statements)

References 32 publications

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“…4A, B ). The preferential incorporation of [ ]oleic acid, to sphingolipids seems to be consistent with the fact that saturated and monounsaturated VLCFAs are predominantly found in sphingolipids ( 10,31 ). This fi nding may help explain the increased levels of monounsaturated VLCFAs (C22:1 and C24:1) seen in the plasma of patients treated with Lorenzo's oil ( 23 ).…”

Section: Lorenzo's Oil Decreases the Cellular Level Of Sm With A Satusupporting

confidence: 67%

Lorenzo's oil inhibits ELOVL1 and lowers the level of sphingomyelin with a saturated very long-chain fatty acid

Sassa

Wakashima

Ohno

et al. 2014

Journal of Lipid Research

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This article is available online at http://www.jlr.org acids (VLCFAs) and have essential physiological functions that cannot be compensated for by LCFAs, such as skin barrier formation, retinal function, myelin maintenance, and spermatogenesis (1)(2)(3)(4)(5). VLCFAs are components of the two important lipid classes, glycerolipids and sphingolipids, which are characterized by their lipid backbone that in the former is a glycerol and in the latter a sphingoid base. Although the sphingoid base is structurally similar to the glycerol with an FA at the sn -1 position, VLCFAs linked to these backbones are strikingly different: Those of glycerolipids are mostly polyunsaturated, whereas those of sphingolipids are saturated and monounsaturated (especially C24). In mammals, a polar head group, phosphocholine or sugar, is attached to the N-acylated sphingoid base (ceramide) forming SM or glycosphingolipid, respectively. Sphingolipids containing VLCFAs have unique cellular functions such as microdomain/raft-mediated signal transduction and cell survival ( 6-8 ). Ceramides with у C26 VLCFAs are also present in the skin and essential for epidermal permeability barrier function ( 3, 9, 10 ).X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder characterized by progressive demyelination and adrenal insuffi ciency ( 11,12 ). The gene mutated in X-ALD is the ABCD1 gene ( 13 ), which encodes a peroxisomal ABC protein responsible for transporting VLCFAs (as VLCFA-CoAs) into peroxisomes ( 14, 15 ) where these FAs are broken down by ␤ -oxidation ( 16 ). The defective ABCD1 protein impairs this normal VLCFA degradation process, resulting in the accumulation of VLCFAs, specifi cally C24:0 and C26:0, in the plasma and tissues ( 11,17 ). The accumulation of these VLCFAs is believed to play a crucial role in the pathogenesis of X-ALD such as infl ammatory demyelination and oxidative damage ( 18,19 ). Therefore, reducing or preventing the accumulation of VLCFAs by either promoting their Abstract X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder caused by impaired degradation of very long-chain fatty acids (VLCFAs) due to mutations in the ABCD1 gene responsible for VLCFA transport into peroxisomes. Lorenzo's oil, a 4:1 mixture of glyceryl trioleate and glyceryl trierucate, has been used to reduce the saturated VLCFA level in the plasma of X-ALD patients; however, the mechanism by which this occurs remains elusive. We report the biochemical characterization of Lorenzo's oil activity toward elongation of very long-chain fatty acid ( ELOVL) 1, the primary enzyme responsible for the synthesis of saturated and monounsaturated VLCFAs. Abbreviations: ELOVL, elongation of very long-chain fatty acid ; LCFA, long-chain fatty acid; UPLC, ultraperformance liquid chromatography; VLCFA, very long-chain fatty acid; X-ALD, X-linked adrenoleukodystrophy .

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Section: Lorenzo's Oil Decreases the Cellular Level Of Sm With A Satusupporting

confidence: 67%

Lorenzo's oil inhibits ELOVL1 and lowers the level of sphingomyelin with a saturated very long-chain fatty acid

Sassa

Wakashima

Ohno

et al. 2014

Journal of Lipid Research

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“…To examine this possibility, we prepared HEK 293T cells producing different sets of ceramides with specific chain lengths by introducing particular combinations of ceramide synthase and FA elongase (ELOVL1 and CERS2, C22-C24 ceramides; ELOVL1 and CERS3, C26 ceramide; and ELOVL4 and CERS3, ≥C26 ceramides) (Fig. 5C) (28,29). Mammals have six ceramide synthases (CERS1-6) and seven FA elongases (ELOVL1-7), and each exhibits characteristic substrate specificity (Fig.…”

Section: Resultsmentioning

confidence: 99%

Essential role of the cytochrome P450 CYP4F22 in the production of acylceramide, the key lipid for skin permeability barrier formation

Ohno

Nakamichi

Ohkuni

et al. 2015

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

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A skin permeability barrier is essential for terrestrial animals, and its impairment causes several cutaneous disorders such as ichthyosis and atopic dermatitis. Although acylceramide is an important lipid for the skin permeability barrier, details of its production have yet to be determined, leaving the molecular mechanism of skin permeability barrier formation unclear. Here we identified the cytochrome P450 gene CYP4F22 (cytochrome P450, family 4, subfamily F, polypeptide 22) as the long-sought fatty acid ω-hydroxylase gene required for acylceramide production. CYP4F22 has been identified as one of the autosomal recessive congenital ichthyosis-causative genes. Ichthyosis-mutant proteins exhibited reduced enzyme activity, indicating correlation between activity and pathology. Furthermore, lipid analysis of a patient with ichthyosis showed a drastic decrease in acylceramide production. We determined that CYP4F22 was a type I membrane protein that locates in the endoplasmic reticulum (ER), suggesting that the ω-hydroxylation occurs on the cytoplasmic side of the ER. The preferred substrate of the CYP4F22 was fatty acids with a carbon chain length of 28 or more (≥C28). In conclusion, our findings demonstrate that CYP4F22 is an ultra-long-chain fatty acid ω-hydroxylase responsible for acylceramide production and provide important insights into the molecular mechanisms of skin permeability barrier formation. Furthermore, based on the results obtained here, we proposed a detailed reaction series for acylceramide production.acylceramide | ceramide | lipid | skin | sphingolipid

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“…Dye exclusion assays were performed using toluidine blue essentially as described elsewhere (26,27). Newborn pups at P0 were incubated with methanol for 5 min and washed in PBS, after which they were incubated with 0.1% toluidine blue for 24 h. Before and after staining, pups were washed with PBS and photographed by a digital camera.…”

Section: Generation Of Aldh3a2mentioning

confidence: 99%

“…H&E Staining-After P0 pups were subjected to perfusion fixation with 3.7% formaldehyde in saline, and skins were isolated and fixed with 3.7% formaldehyde in PBS at 4°C for Ͼ48 h. Fixed skins were then subjected to dehydration, paraffin embedding, preparation of sections, deparaffinization, and staining with hematoxylin and then eosin using an automatic staining system (Tissue-Tek DRS 2000, Sakura, Torrance, CA) as described previously (26). Bright field images were captured using a Leika DM5000B microscope equipped with a DFC295 digital color camera (Leica Microsystems, Wetzlar, Germany).…”

Section: Generation Of Aldh3a2mentioning

confidence: 99%

Disruption of the Sjögren-Larsson Syndrome Gene Aldh3a2 in Mice Increases Keratinocyte Growth and Retards Skin Barrier Recovery

Naganuma

Takagi

Kanetake

et al. 2016

Journal of Biological Chemistry

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The fatty aldehyde dehydrogenase (FALDH) ALDH3A2 is the causative gene of Sjögren Larsson syndrome (SLS Sjögren-Larsson syndrome (SLS)2 is a hereditary neurocutaneous disorder caused by mutations in the fatty aldehyde dehydrogenase (FALDH) gene, ALDH3A2. The major symptoms of SLS are mental retardation, spastic di-or tetraplegia, and ichthyosis, with crystalline macular dystrophy sometimes comorbid (1). ALDH3A2 catalyzes the conversion of fatty aldehydes with medium-chain (MC) to very-long-chain fatty acids (FA) (MC, C5-C10; long-chain (LC), C11-C20; and very-longchain, ՆC21), with the most preferred substrates being C16 and C18 aldehydes (2, 3). To date, more than 70 mutations have been found in the ALDH3A2 gene of SLS patients, and most of them cause Ͼ90% reduction in enzyme activity (4). Because aldehyde molecules are reactive and toxic in general, it is considered that accumulated fatty aldehydes cause the SLS pathology by reacting with certain important proteins in the nervous system and epidermis and compromising their functions. Furthermore, the literature lacks a detailed description of the characteristics of Aldh3a2 knock-out mice.The skin symptom ichthyosis is characterized by dry, thickened, and scaly skin, often likened to fish scales, and is caused by a skin permeability barrier defect related to multilayered lipids (lipid lamellae) in the epidermis. The epidermis is composed of four cell layers, the stratum basale, stratum spinosum, stratum granulosum, and the stratum corneum, the last of which is the site of these lipid lamellae, and accordingly has the most important role in skin barrier formation (5, 6). Keratinocytes proliferate in the stratum basale and migrate outward, differentiating into cell layer-specific cell types. The major lipid components of lipid lamellae are ceramides, cholesterol, and FAs, with ceramides being the most abundant (5, 6). A variety of ceramide species exist in the epidermis. Among them, acylceramides are a class of epidermis-specific ceramides that play an essential role in skin barrier formation (7,8). Ceramides are normally composed of a long-chain base (LCB) and a FA (9). However, acylceramides contain an additional hydrophobic chain (linoleic acid), which is esterified with the hydroxylated -carbon of the FA. In the epidermis of SLS patients, some ceramide species, including the acylceramide EOS (a combination of an esterified -hydroxy FA and the LCB sphingosine), are greatly reduced (10).Several metabolic pathways generate the substrates of ALDH3A2, fatty aldehydes. These include metabolic pathways of leukotriene B 4 , diet-derived phytol, plasmalogens, and fatty alcohols (11)(12)(13)(14)(15). Furthermore, we recently revealed that metabolism of LCBs also generates fatty aldehydes, i.e. hexadecanal (C16:0 aldehyde) from dihydrosphingosine (DHS) and

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Impaired Epidermal Permeability Barrier in Mice Lacking Elovl1, the Gene Responsible for Very-Long-Chain Fatty Acid Production

Cited by 143 publications

References 32 publications

Lorenzo's oil inhibits ELOVL1 and lowers the level of sphingomyelin with a saturated very long-chain fatty acid

Lorenzo's oil inhibits ELOVL1 and lowers the level of sphingomyelin with a saturated very long-chain fatty acid

Essential role of the cytochrome P450 CYP4F22 in the production of acylceramide, the key lipid for skin permeability barrier formation

Disruption of the Sjögren-Larsson Syndrome Gene Aldh3a2 in Mice Increases Keratinocyte Growth and Retards Skin Barrier Recovery

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