Decreased Level of Ceramides in Stratum Corneum of Atopic Dermatitis: An Etiologic Factor in Atopic Dry Skin?

Imokawa, Genji; Abe, Akihito; Jin, Kumi; Higaki, Yuko; Kawashima, Makoto; Hidano, Akira

doi:10.1111/1523-1747.ep12470233

Cited by 952 publications

(805 citation statements)

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“…The importance of acylceramide in the maintenance of the barrier function is also supported by our previous evidence ) that the topical application of pseudoacylceramide-containing ester-linked linoleic acid to the skin of essential fatty acid-deficient rats can restore the disturbed barrier function as revealed by the increased transepidermal water loss and epidermal hyperplasia. In skin with AD, we have consistently found that the acylceramide deficiency exists to the highest degree among several ceramide species, being predominantly attributable to the barrier disruption constitutively seen even in the nonlesional skin of patients with AD (Imokawa et al, 1991).…”

Section: Discussionmentioning

confidence: 83%

“…Thus, it is likely that acylceramides (ceramides 1 or 4) are synthesized not by hydrolysis of SM but through pathways involving deglucosylation of acylglucosylceramides by GlCdase. On the basis of these findings, the acylceramide deficiency observed in AD (Imokawa et al, 1991) could not be explained in terms of the up-regulation of SM deacylase. In this regard, we supposed the possibility that if, like SM deacylase, an unknown enzyme tentatively termed GC deacylase, capable of catalyzing N-deacylation of GC, is highly expressed in the epidermis of patients with AD, then this abnormality may lead to the acylceramide deficiency.…”

Section: Glucosylceramide Deacylase and Glucosylsphingosine In Atopicmentioning

confidence: 81%

“…A deficiency of ceramides in the stratum corneum is an causative factor of the barrier-disrupted and dry skin of patients with atopic dermatitis (AD) (Imokawa et al, 1991). This dysfunction of the stratum corneum leads to a high vulnerability to irritants or allergens, which results in the induction, recurrence, or refractory nature of the dermatitis.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, collectively these results strongly suggest the physiologic relevance of GC deacylase to the acylceramide deficiency seen in the stratum corneum of patients with AD. (Lab Invest 2003, 83:397-408).A deficiency of ceramides in the stratum corneum is an causative factor of the barrier-disrupted and dry skin of patients with atopic dermatitis (AD) (Imokawa et al, 1991). This dysfunction of the stratum corneum leads to a high vulnerability to irritants or allergens, which results in the induction, recurrence, or refractory nature of the dermatitis.…”

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confidence: 99%

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Abnormal Expression of the Novel Epidermal Enzyme, Glucosylceramide Deacylase, and the Accumulation of its Enzymatic Reaction Product, Glucosylsphingosine, in the Skin of Patients with Atopic Dermatitis

Ishibashi

Arikawa

Okamoto

et al. 2003

Laboratory Investigation

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SUMMARY:To clarify mechanisms underlying acylceramide deficiency as an causative factor of the permeability barrier disruption seen in the skin of patients with atopic dermatitis (AD), we hypothesized and then demonstrated the presence of a novel epidermal enzyme, termed glucosylceramide (GC) deacylase. This enzyme hydrolyzes (acyl)GC at the N-acyl site to yield its lysoform, glucosylsphingosine (GS), instead of the formation of (acyl)ceramides by ␤-glucocerebrosidase. Assays of enzymatic activity using [palmitic acid-14 C] GC as a substrate revealed that extracts from the stratum corneum and from the epidermis (but not from the dermis) of patients with AD have the significantly higher potential to hydrolyze GC at the N-acyl site to release 14 C-labeled free fatty acid than of healthy controls. To determine the in vivo physiologic function of this novel enzyme, we measured the metabolic product GS in the upper stratum corneum. In both the involved and the uninvolved stratum corneum from patients with AD, there were significant increases in the amounts of GS compared with healthy controls and there was a significant inverse correlation with the decreased content of ceramides or ceramide-1 (acylceramide). Thus, collectively these results strongly suggest the physiologic relevance of GC deacylase to the acylceramide deficiency seen in the stratum corneum of patients with AD. (Lab Invest 2003, 83:397-408).A deficiency of ceramides in the stratum corneum is an causative factor of the barrier-disrupted and dry skin of patients with atopic dermatitis (AD) (Imokawa et al, 1991). This dysfunction of the stratum corneum leads to a high vulnerability to irritants or allergens, which results in the induction, recurrence, or refractory nature of the dermatitis. Thus, it is intriguing to determine the biochemical mechanism(s) underlying the ceramide deficiency because it may be linked to the physiopathogenesis of AD. In the epidermis of patients with AD, we have previously demonstrated the accentuated expression of a hitherto undiscovered epidermal enzyme, termed sphingomyelin (SM) deacylase, which was associated with the reduced ceramide mass in the stratum corneum as a result of its competition with the ceramideproducing enzyme sphingomyelinase (SMase) for the common substrate SM Murata et al, 1996). Recently, it was reported that omega-OH ceramide, an important acylceramide precursor, does not derive from SM in the mammalian stratum corneum, which suggests that it derives solely from glucosylceramide (GC) precursors (Uchida et al, 2000). Thus, it is likely that acylceramides are biosynthesized not by the hydrolysis of SM but through pathways involving the deglucosylation of acylglucosylceramides by ␤-glucocerebrosidase (GlCdase). On the basis of these findings, the acylceramide deficiency observed in AD could not be explained in terms of the up-regulation of SM deacylase. As a resolution for this discrepancy, we hypothesized the existence of a novel epidermal enzyme, termed here GC deacylase, which hydrolyzes (acyl)GC at t...

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Section: Discussionmentioning

confidence: 83%

Section: Glucosylceramide Deacylase and Glucosylsphingosine In Atopicmentioning

confidence: 81%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Abnormal Expression of the Novel Epidermal Enzyme, Glucosylceramide Deacylase, and the Accumulation of its Enzymatic Reaction Product, Glucosylsphingosine, in the Skin of Patients with Atopic Dermatitis

Ishibashi

Arikawa

Okamoto

et al. 2003

Laboratory Investigation

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“…by stripping [8][9][10], scraping [11], skin rinsing [3,12] or with an extraction chamber [11,13]. Whatever the approach, the three lipid classes present in the SC were recovered: free fatty acids, Cho and ceramides.…”

Section: Introductionmentioning

confidence: 99%

Microanalytical systems for separations of stratum corneum ceramides

et al. 2006

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Original PaperMicroanalytical systems for separations of stratum corneum ceramidesThe small amount of lipids from human skin obtained with noninvasive sampling method led us to investigate microanalytical separation techniques. The lipid class analysis was performed with a micro polyvinyl alcohol-silica (PVA-Silm) column. The gradient elution was from heptane to acetone/butanol 90:10 v/v in 4%/min at 78 lL/ min. In addition an evaporative light scattering detector (ELSD) was modified for micro-LC. All solvents contained 0.1% of triethylamine and formic acid in stoichiometric amount, which increased the ELSD response. In these conditions, the cholesterol eluted before free fatty acid, and squalene and triglycerides close to the dead volume. The various ceramide classes eluted following the order of the increased number of hydroxyl groups. The LOD for ceramides was 2.2 ng. The advantages of this method are the use of a normal stationary phase more reliable due to its chemical stability, its surface homogeneity and its development in microchromatography without chlorinated solvents which offers small LOD and the whole profile of lipids present in stratum corneum (SC). A method using a narrow-bore PVA-Sil column was used to collect ceramide fraction. Then the molecular species were analysed with a porous graphitic carbon column in capillary LC using a gradient from CH 3 OH/CHCl 3 70:30 v/v to CHCl 3 at 2%/min with a flow rate at 5 lL/min. The LOD obtained for ceramide was 1 ng. Both methods were assessed with SC samples obtained by rinsing a 5.7 cm 2 area of the forearm with 25 mL of ethanol. IntroductionStratum corneum (SC) consists of corneocytes organized in a matrix of highly ordered multilamellar lipid sheets [1,2]. For the structural and physical properties of this lipid arrangement, SC is considered to play an essential role in the skin barrier function. Ceramides constitute 50% of this lipid barrier. Free fatty acid and cholesterol (Cho) constitute the remaining lipid classes composing this lipid barrier. The ceramide classes are highly heterogeneous in structure due to the sphingoid base and fatty acid moieties constituting these amide molecules. They differ by a different number of hydroxyl groups and carbon double bonds, and the chain length [3]. This structural heterogeneity is an important element to study the lipid barrier property. The nature of the structural difference between molecular species included in each lipid class is apolar. Therefore, apolar stationary phases are required for their discrimination such as octadecyl bonded silica [4][5][6] or porous graphitic carbon (PGC) [7]. This latter column provides original selectivity between molecular species. However, to apply such analytical methods to skin samples, the lipids should be previously extracted and the various lipid classes separated.Several noninvasive methods for extraction of lipids from SC exist, e.g. by stripping [8][9][10], scraping [11], skin rinsing [3,12] or with an extraction chamber [11,13]. Whatever the approach, the three...

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