Ceramides in the Skin Lipid Membranes: Length Matters

Abstract

Ceramides are essential constituents of the skin barrier that allow humans to live on dry land. Reduced levels of ceramides have been associated with skin diseases, e.g., atopic dermatitis. However, the structural requirements and mechanisms of action of ceramides are not fully understood. Here, we report the effects of ceramide acyl chain length on the permeabilities and biophysics of lipid membranes composed of ceramides (or free sphingosine), fatty acids, cholesterol, and cholesterol sulfate. Short-chain ceramides increased the permeability of the lipid membranes compared to a long-chain ceramide with maxima at 4-6 carbons in the acyl. By a combination of differential scanning calorimetry, Fourier transform infrared spectroscopy, X-ray diffraction, Langmuir monolayers, and atomic force microscopy, we found that the reason for this effect in short ceramides was a lower proportion of tight orthorhombic packing and phase separation of continuous short ceramide-enriched domains with shorter lamellar periodicity compared to native long ceramides. Thus, long acyl chains in ceramides are essential for the formation of tightly packed impermeable lipid lamellae. Moreover, the model skin lipid membranes are a valuable tool to study the relationships between the lipid structure and composition, lipid organization, and the membrane permeability.

The barrier function of organotypic non-melanoma skin cancer models

“…3C). The decreased amount of very long CER NS/ NdS in the NMSC models likely increased the permeability of NMSC models as well, since reduced portions of very long CER enhance theophylline permeability in a SC lipid model [32]. Although our study supports the hypothesis of an impaired skin barrier function of NMSC lesions, large-scale studies with AK and cSCC patients are needed to finally verify permeability of lesional skin.…”

“…The reduced fraction of orthorhombic lateral lipid packing in the SC of NMSC models contributed to the impaired skin barrier function. Altered lateral lipid packing is generally paralleled by a changed SC lipid profile [32]. We found decreased cholesterol and increased phospholipid levels as well as a shift in ceramide subclasses to higher levels of phytoceramides.…”

Probing the Role of the Ceramide Acyl Chain Length and Sphingosine Unsaturation in Model Skin Barrier Lipid Mixtures by 2H Solid-State NMR Spectroscopy

“…The crystallinity of Cer and LA is in agreement with recent FTIR data from the mixture of Cer[NS24]/LA/Chol 43 and also of Cer[NS24]/LA/Chol/Chol sulfate. 20 Such systems are characterized by orthorhombic chain packing, which largely restricts the permeability of the SC in the skin. 44,45 The loss of the C4 trans double bond in the Cer[NDS24]-containing mixture has dramatic consequences on its phase behavior.…”

“…Gel-state bilayers are more permeable than crystalline SC models. 20 Also, the LA in the mixture is a bit less crystalline as in the Cer[NS24]-containing mixture. Gel-phase formation was not observed for the LA in the mixture.…”

Effects of Concentrations on the Transdermal Permeation Enhancing Mechanisms of Borneol: A Coarse-Grained Molecular Dynamics Simulation on Mixed-Bilayer Membranes

“…Over 300 ceramides have been identified in SC with fatty acid lengths varying from 16 to 34 carbons. Among them, Ceramide- N -sphingosine (CER NS) is the most abundant species in human SC, and the most commonly studied ceramide in lipid model of SC [35,36,37]. Cholesterol is also an essential component of the SC.…”