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.
Highlights
The primary function of mammalian skin is to provide a semipermeable interface between the body and the external environment, i.e., prevent water loss and the penetration of exogenous, potentially harmful compounds [1]
We studied the microstructure of our lipid models using X-ray Diffraction (XRD)
This repeat distance is close to the so-called short periodicity phase (d = 5.3–6.5 nm) found in model skin lipid membranes [9,16,30] and human stratum corneum (SC) [31,32]
Summary
The primary function of mammalian skin is to provide a semipermeable interface between the body and the external environment, i.e., prevent water loss and the penetration of exogenous, potentially harmful compounds [1]. The composition and organization of these SC lipids are somewhat unusual: the dominant lipids comprise ceramides (Cers), cholesterol (Chol), and free fatty acids (FFAs), which form multiple lamellae of tightly packed lipids with mostly rigid chains [2,3,4,5]. The SC Cers consist of a sphingoid base (sphingosine (S), dihydrosphingosine (dS), phytosphingosine (P), and 6-hydroxysphingosine (H)) amidelinked to fatty acid acyl (which is non-substituted (N), α-hydroxylated (A), ω-hydroxylated (O), or bears the ω-linoleyloxy group (EO)). The shorthand nomenclature [6] uses the combination of the letters in parentheses; for example, N-α-hydroxyacyl sphingosine is Cer AS. The behavior of skin-identical Cers with very long non-hydroxylated acyl chains has been widely explored in model biological membranes. The absence of a trans-double bond in Cer precursors, dihydroceramides, that form approximately 12% of Cers in healthy SC [7]
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