Deficiency of Epidermal Protein-Bound ω-Hydroxyceramides in Atopic Dermatitis

Abstract

Atopic dermatitis is a common skin disease of unknown etiology with an impaired permeability barrier function. To learn more about the molecular pathology in lesional skin, we analyzed levels of free extractable as well as protein-bound barrier lipids in the epidermis of atopic dermatitis subjects. The amount of protein-bound omega-hydroxyceramides in healthy epidermis comprised 46-53 wt% of total protein-bound lipids, whereas this percentage was decreased to 23-28 wt% in nonlesional areas and even down to 10-25 wt% in affected atopic skin areas of the subjects. Furthermore, the partial amount of free extractable very long chain fatty acids with more than 24 carbon atoms was reduced in affected regions down to 25 wt% and in nonlesional regions of the atopic dermatitis subjects down to 40 wt% compared to healthy controls. This "hydrocarbon chain length deficiency" regarding the barrier lipids in atopic skin was supported by metabolic labeling studies with [14C]-serine in cultured epidermis. The biosynthesis of free glucosylceramides and free ceramides was remarkably decreased in affected skin areas of the atopic subjects compared to healthy control subjects. Especially affected were the de novo syntheses of ceramide 4 (i.e., ceramide EOH, consisting of a very long chain N-acyl omega-hydroxy fatty acid esterified with linoleic acid and 6-hydroxysphingosine as sphingoid base) and ceramide 3 (ceramide NP, consisting of a nonhydroxy N-acyl fatty acid and phytosphingosine). In conclusion, this study revealed that the lesional epidermis in atopic dermatitis has considerable deficiencies within main barrier lipid components, which may contribute to the severely damaged permeability barrier.

Gromwell (Lithospermum erythrorhizon) Supplementation Enhances Epidermal Levels of Ceramides, Glucosylceramides, β-Glucocerebrosidase, and Acidic Sphingomyelinase in NC/Nga Mice

“…1A), as extensively reported previously. 9,17,18 The total Cer in group LE was higher than that in group CA, and was similar to that in group C, which is consistent with our previous reports. 9 Cer bearing structural moieties of amide-linked non-hydroxy acid, a-hydroxy acid, or x-hydroxy acid as well as esterlinked fatty acid (FA) on sphingoid bases are critical to FIG.…”

“…In AD, the decreased levels of Cer, GlcCer, or SM parallel the reductions in de novo Cer synthesis, the SMase activity, and/or the ceramidase activity. 18,23,24 Moreover, a deficiency of GlcCer synthase or SM synthase, enzymes involved in GlcCer or SM synthesis, respectively, results in significant reductions of GlcCer and/or SM, ultimately decreasing Cer levels. 10,25 Alternatively, unusual expression of SM deacylase, which metabolizes SM to sphingosyl phosphorylcholine, could also underlie the decreased levels of Cer in the epidermal lesions of AD patients.…”

Thematic Review Series: Skin Lipids. Antimicrobial lipids at the skin surface

“…The skin surface of atopic individuals is often colonized by S. aureus, and an inverse correlation has been demonstrated between the free sphingosine level and the quantitative carriage of S. aureus in this condition (60). It has been noted that the level of covalently bound v-hydroxyceramides is reduced in the stratum corneum of atopic individuals (76). This may reflect the action of a ceramidase on the covalently bound v-hydroxyceramides to release free sphingoid bases and to leave behind v-hydroxyacids attached to the cornified envelope.…”

Cloning and Characterization of a Mouse Endoplasmic Reticulum Alkaline Ceramidase

“…It has been shown that extracellular ceramides and complex sphingolipids play important roles in forming the permeability barrier of skin (24). Macheleidt et al (27) showed that very long chain ceramides are reduced significantly in the epidermis of atopic dermatitis patients, suggesting that the very long chain ceramides have an important role in regulating the permeability barrier function. maCER1 may have a role in regulating the barrier function by regulating the levels of very long chain ceramides in skin.…”