Effects of (R)- and (S)-α-Hydroxylation of Acyl Chains in Sphingosine, Dihydrosphingosine, and Phytosphingosine Ceramides on Phase Behavior and Permeability of Skin Lipid Models

Abstract

Ceramides (Cers) with α-hydroxylated acyl chains comprise about a third of all extractable skin Cers and are required for permeability barrier homeostasis. We have probed here the effects of Cer hydroxylation on their behavior in lipid models comprising the major SC lipids, Cer/free fatty acids (C 16-C 24)/cholesterol, and a minor component, cholesteryl sulfate. Namely, Cers with (R)-α-hydroxy lignoceroyl chains attached to sphingosine (Cer AS), dihydrosphingosine (Cer AdS), and phytosphingosine (Cer AP) were compared to their unnatural (S)-diastereomers and to Cers with non-hydroxylated lignoceroyl chains attached to sphingosine (Cer NS), dihydrosphingosine (Cer NdS), and phytosphingosine (Cer NP). By comparing several biophysical parameters (lamellar organization by X-ray diffraction, chain order, lateral packing, phase transitions, and lipid mixing by infrared spectroscopy using deuterated lipids) and the permeabilities of these models (water loss and two permeability markers), we conclude that there is no general or common consequence of Cer α-hydroxylation. Instead, we found a rich mix of effects, highly dependent on the sphingoid base chain, configuration at the α-carbon, and permeability marker used. We found that the model membranes with unnatural Cer (S)-AS have fewer orthorhombically packed lipid chains than those based on the (R)-diastereomer. In addition, physiological (R)-configuration decreases the permeability of membranes, with Cer (R)-AdS to theophylline, and increases the lipid chain order in model systems with natural Cer (R)-AP. Thus, each Cer subclass makes a distinct contribution to the structural organization and function of the skin lipid barrier.

Multiscale Simulation of Ternary Stratum Corneum Lipid Mixtures: Effects of Cholesterol Composition

“…Comparison of Bilayer and Multilayer Structures. As noted earlier, experimental SC lipid membrane systems exhibit multilayer structures, which, for a typical lipid deposition of between 0.9 and 1.5 mg/cm 2 , 18,76,77 produce lipid membranes that are more than 10 μm thick. This corresponds to a stack of more than a thousand, ∼6 nm SPP-type bilayers.…”

Distribution of Domains Formed by Lateral Packing of Intercellular Lipid in the Stratum Corneum

“…The results are also consistent with a study of lipid model membranes, which reported that alphahydroxylation of CERs (CER[AS] and CER[AP]) decreased resistance to water loss. 38) On the other hand, the finding that the distribution of S-chain lengths in CER[ADS] and CER[AP] differed between the high-and low-TEWL groups (Table 2) suggests that the difference in the distribution of S-chain lengths affects the proportion of domains formed by packing structures. Figure 7 shows that in the chain length distribution of CER[ADS], there was generally a low proportion of long C22 saturated hydrocarbon chains in the high-TEWL group.…”

Comment on “Clinical significance of the water retention and barrier function‐improving capabilities of ceramide‐containing formulations: A qualitative review”

“…2S, 3R-sphingosine and 2S, 3S, 4R-phytosphingosine) together with Rα-hydroxy fatty acids have recently been studied. 5,6 For at least one marketed ceramide, AP, the α-hydroxy fatty acid component consists of the two diastereomers of which the natural R-isomer promotes tighter lipid packing and the authors conclude that it should be preferred compared with the unnatural S-isomer or the racemic version. 6 The representative structures of other types of molecules (pseudoceramides) that are used in skin-care products are shown in Figure 1b.…”