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Ceramides (Cer) based on 6-hydroxysphingosine are important components of the human skin barrier, the stratum corneum. Although diminished concentrations of 6-hydroxyCer have been detected in skin diseases such as atopic dermatitis, our knowledge on these unusual sphingolipids, which have only been found in the skin, is limited. In this work, we investigate the biophysical behavior of N-lignoceroyl-6-hydroxysphingosine (Cer NH) in multilamellar lipid membranes composed of Cer/free fatty acids (FFAs) (C16-C24)/cholesterol/cholesteryl sulfate. To probe the Cer structure-activity relationships, we compared Cer NH membranes with membranes containing Cer with sphingosine (Cer NS), dihydrosphingosine, and phytosphingosine (Cer NP), all with the same acyl chain length (C24). Compared with Cer NS, 6-hydroxylation of Cer not only increased membrane water loss and permeability in a lipophilic model compound but also dramatically increased the membrane opposition to electrical current, which is proportional to the flux of ions. Infrared spectroscopy revealed that Cer hydroxylation (in either Cer NH or Cer NP) increased the main transition temperature of the membrane but prevented good Cer mixing with FFAs. X-ray powder diffraction showed not only lamellar phases with shorter periodicity upon Cer hydroxylation but also the formation of an unusually long periodicity phase (d = 10.6 nm) in Cer NH-containing membranes. Thus, 6-hydroxyCer behaves differently from sphingosine- and phytosphingosine-based Cer. In particular, the ability to form a long-periodicity lamellar phase and highly limited permeability to ions indicate the manner in which 6-hydroxylated Cer contribute to the skin barrier function.

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Omega-O-acylceramides (acylCer), a subclass of sphingolipids with an ultralong N-acyl chain (from 20 to 38 carbons, most usually 30 and 32 carbons), are crucial components of the skin permeability barrier. AcylCer are involved in the formation of the long periodicity lamellar phase (LPP, 12-13 nm), which is essential for preventing water loss from the body. Lower levels of acylCer and LPP accompany skin diseases, such as atopic dermatitis, lamellar ichthyosis, and psoriasis. We studied how the concentration and structure of acylCer influence the organization and permeability barrier properties of model lipid membranes. For simple model membranes composed of the sphingosine-containing acylCer (EOS), N-lignoceroyl sphingosine, lignoceric acid, cholesterol (Chol), and cholesteryl sulfate (CholS), the LPP formed at 10% Cer EOS (of the total Cer) and the short periodicity phase disappeared at 30% Cer EOS. Surprisingly, membranes with the LPP had higher permeabilities than the control membrane without acylCer. In the complex models consisting of acylCer (EOS, phytosphingosine EOP, dihydrosphingosine EOdS, or their mixture; at 10% of the total Cer), a six-component Cer mixture, a free fatty acid mixture, cholesterol (Chol), and cholesteryl sulfate (CholS), acylCer decreased the membrane permeability to model permeants (with the strongest effects for acylCer EOP and EOdS) when compared with the permeability of the control membrane without acylCer. However, in the complex model, only a mixture of acylCer EOS, EOdS, and EOP and not the individual acylCer formed both the LPP and orthorhombic chain packing at the 10% level. Thus, the relationships between acylCer, LPP formation, and permeability barrier function are not trivial. Lipid heterogeneity is essential-only the most complex model with nine Cer subclasses mimicked both the organization and permeability of stratum corneum lipid membranes.