Abnormal Expression of Sphingomyelin Acylase in Atopic Dermatitis: An Etiologic Factor for Ceramide Deficiency?

Abstract

Previously, we demonstrated that there is a marked reduction in the amount of ceramide in the stratum corneum of both lesional and nonlesional forearms in atopic dermatitis (AD), suggesting that an insufficiency of ceramides in the stratum corneum is an etiologic factor in atopic dry and barrier-disrupted skin. In this study, we investigated, as a possible mechanism involved in the ceramide deficiency, whether sphingomyelin (SM) metabolism is altered in AD as compared to normal controls. In stripped stratum corneum and biopsied whole epidermis of patients with AD, SM hydrolysis as measured at pH 4.7 using [choline-methyl-14C]sphingomyelin as a substrate were markedly increased by 27- and 7-fold, respectively. Radio-thin-layer chromatography of the reaction products revealed that, whereas the SM hydrolysis in age-matched normal controls were associated with sphingomyelinase (SMase) that degrades SM to yield ceramides and phosphorylcholine (PC), most of the SM hydrolysis detected in AD were attributable not to the SMase but to a hitherto undiscovered epidermal enzyme, SM acylase, which releases free fatty acid and sphingosyl-PC (Sph-PC) instead of ceramides. The potential of this acylase-like enzyme to generate Sph-PC through SM hydrolysis was corroborated by thin-layer chromatographic analysis of the reaction products obtained using porcine kidney acylase, followed by high-performance liquid chromatography-mass spectrometry. Furthermore, Sph-PC was also detected by high-performance liquid chromatography-mass spectrometry after incubation of SM with atopic stratum corneum samples. On the other hand, the stratum corneum of patients with contact dermatitis or chronic eczema exhibited neither increased SM hydrolysis nor the generation of Sph-PC upon radio-thin-layer chromatographic analysis. These findings suggest that SM metabolism is altered in AD, resulting in a decrease in levels of ceramides, which could be an etiologic factor in the continuous generation of atopic dry and barrier disrupted skin observed in AD.

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

“…9). In contrast, in patients with chronic eczema or contact dermatitis, there was no significant up-regulation in the activity of SM deacylase Murata et al, 1996) or in the content of SPC in the stratum corneum compared with healthy controls (Okamoto et al, 1999), thus indicating that the up-regulated activity of SM deacylase is not a The amount of total CER (A) and ceramide-1 (acylceramide) (B) in the upper stratum corneum from patients with AD and healthy controls. The CER levels in the same individual used for correlation analysis were compared between AD and control.…”

“…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).…”

“…9) that a novel sphingolipid metabolizing enzyme, termed SM deacylase, is highly expressed in the epidermis of patients with AD, which results in the interruption of ceramide production Murata et al, 1996). This was based on evidence that there is no abnormality in the activities of other ceramide-generating or -degrading enzymes, including acid SMase Jin et al, 1994).…”

Epidermal tight junctions in health and disease

“…The SC is dysfunctional in AD as the result of one or more of the following defects: reduced levels of SC lipids. [94][95][96] acquired or genetic defects in structural proteins such as filaggrin (FLG) [97][98][99] and/or scratching that is a cardinal feature of the disease. De Benedetto et al have identified reduced expression of cldn-1 and -23, 25 and more recently cldn-4 in clinically uninvolved, nonlesional AD skin of a Northern American cohort (De Benedetto & Beck unpublished).…”

The Effect of Gromwell (Lithospermum erythrorhizon) Extract on the Stratum Corneum Hydration and Ceramides Content in Atopic Dermatitis Patients

“…Extremely high activities of ceramidase 7 and sphingomyelin deacylase 35 , which hydrolyze sphingomyelin into sphingophosphorylcholine and free fatty acid, have been demonstrated to be the metabolic features leading to low levels of ceramides in the SC in AD. The patients with AD in preclinical stages have altered proportions of ceramides in their skin 36,37 as a result of alterations in the activity of enzymes involved in the biosynthetic pathways of ceramide production 38,39 . IgE (IU/ml)…”