An update on molecular aspects of the non‐syndromic ichthyoses

Akiyama, Masashi; Shimizu, Hiroshi

doi:10.1111/j.1600-0625.2007.00691.x

Cited by 87 publications

(63 citation statements)

References 111 publications

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“…1073/pnas.1503491112/-/DCSupplemental. 4)/ICHTHYIN, CYP4F22/FLJ39501, LIPN (lipase, family member N), and PNPLA1 (patatin-like phospholipase domain containing 1) (16,19). The exact functions of NIPAL4, LIPN, and PNPLA1 are currently unclear.…”

Section: Significancementioning

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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144

130

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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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Section: Significancementioning

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.

Self Cite

144

130

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“…[1][2][3] During the past few years, much progress has been made in defining the molecular basis of these disorders, and in establishing genotype-phenotype correlations. [4][5][6][7][8][9][10][11] However, there is no universally accepted terminology and classification of the diseases considered under the umbrella term ''ichthyosis.'' Classification schemes and terminology continue to vary greatly among European, North American, and Asian countries.…”

mentioning

confidence: 99%

Revised nomenclature and classification of inherited ichthyoses: Results of the First Ichthyosis Consensus Conference in Sorèze 2009

Oji

Tadini

Akiyama

et al. 2010

Journal of the American Academy of Dermatology

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“…This phenotype is associated with accelerated transepidermal water loss that reflects defects in water barrier function (2) and thus resembles the human genetic disorders of ichthyosis, diseases with a dry, thickened, scaly skin (3,4). Linoleate (C18:2) is by far the most abundant EFA in the epidermis, being mainly esterified to the -hydroxyl of the amide-linked very long chain fatty acid (VLFA) in a unique class of ceramides, namely esterified omega-hydroxyacyl-sphingosine (EOS) (5).…”

mentioning

confidence: 99%

Lipoxygenases Mediate the Effect of Essential Fatty Acid in Skin Barrier Formation

Zheng

Yin

Boeglin

et al. 2011

Journal of Biological Chemistry

138

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A barrier to water loss is vital to maintaining life on dry land. Formation of the mammalian skin barrier requires both the essential fatty acid linoleate and the two lipoxygenases 12R-lipoxygenase (12R-LOX) and epidermal lipoxygenase-3 (eLOX3), although their roles are poorly understood. Linoleate occurs in O-linoleoyl--hydroxyceramide, which, after hydrolysis of the linoleate moiety, is covalently attached to protein via the free -hydroxyl of the ceramide, forming the corneocyte lipid envelope, a scaffold between lipid and protein that helps seal the barrier. Here we show using HPLC-UV, LC-MS, GC-MS, and 1 H NMR that O-linoleoyl--hydroxyceramide is oxygenated in a regio-and stereospecific fashion by the consecutive actions of 12R-LOX and eLOX3 and that these products occur naturally in pig and mouse epidermis. 12R-LOX forms 9R-hydroperoxy-linoleoyl--hydroxyceramide, further converted by eLOX3 to specific epoxyalcohol (9R,10R-trans-epoxy-11E-13R-hydroxy) and 9-keto-10E,12Z esters of the ceramide; an epoxy-ketone derivative (9R,10R-trans-epoxy-11E-13-keto) is the most prominent oxidized ceramide in mouse skin. These products are absent in 12R-LOX-deficient mice, which crucially display a near total absence of protein-bound -hydroxyceramides and of the corneocyte lipid envelope and die shortly after birth from transepidermal water loss. We conclude that oxygenation of O-linoleoyl--hydroxyceramide is required to facilitate the ester hydrolysis and allow bonding of the -hydroxyceramide to protein, providing a coherent explanation for the roles of multiple components in epidermal barrier function. Our study uncovers a hitherto unknown biochemical pathway in which the enzymic oxygenation of ceramides is involved in building a crucial structure of the epidermal barrier.

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An update on molecular aspects of the non‐syndromic ichthyoses

Abstract: Ichthyosis includes a

Cited by 87 publications

References 111 publications

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

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

Revised nomenclature and classification of inherited ichthyoses: Results of the First Ichthyosis Consensus Conference in Sorèze 2009

Lipoxygenases Mediate the Effect of Essential Fatty Acid in Skin Barrier Formation

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