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Behavior of 1-Deoxy-, 3-Deoxy- and N-Methyl-Ceramides in Skin Barrier Lipid Models.

ABSTRACT: Ceramides (Cer) are essential components of the skin permeability barrier. To probe the role of Cer polar head groups involved in the interfacial hydrogen bonding, the N-lignoceroyl sphingosine polar head was modified by removing the hydroxyls in C-1 (1-deoxy-Cer) or C-3 positions (3-deoxy-Cer) and by N-methylation of amide group (N-Me-Cer). Multilamellar skin lipid models were prepared as equimolar mixtures of Cer, lignoceric acid and cholesterol, with 5 wt% cholesteryl sulfate. In the 1-deoxy-Cer-based models, the lipid species were separated into highly ordered domains (as found by X-ray diffraction and infrared spectroscopy) resulting in similar water loss but 4-5-fold higher permeability to model substances compared to control with natural Cer. In contrast, 3-deoxy-Cer did not change lipid chain order but promoted the formation of a well-organized structure with a 10.8 nm repeat period. Yet both lipid models comprising deoxy-Cer had similar permeabilities to all markers. N-Methylation of Cer decreased lipid chain order, led to phase separation, and improved cholesterol miscibility in the lipid membranes, resulting in 3-fold increased water loss and 10-fold increased permeability to model compounds compared to control. Thus, the C-1 and C-3 hydroxyls and amide group, which are common to all Cer subclasses, considerably affect lipid miscibility and chain order, formation of periodical nanostructures, and permeability of the skin barrier lipid models.

SUBMITTER: Kovacik A

PROVIDER: S-EPMC7051948 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Increased Levels of Short-Chain Ceramides Modify the Lipid Organization and Reduce the Lipid Barrier of Skin Model Membranes.

Project description:The skin barrier function is attributed to the stratum corneum (SC) intercellular lipid matrix, which is composed primarily of ceramides (CERs), free fatty acids, and cholesterol. These lipids are organized in two lamellar phases: the short and long periodicity phases (SPP and LPP), respectively. The LPP is considered important for the skin barrier function. High levels of short-chain CERs are observed in various inflammatory skin diseases and have been correlated with barrier dysfunction. In this research, we investigated how the increase in the fraction of the short-chain CER with a nonhydroxy C16 acyl chain linked to a C18 sphingosine base CER NS(C16) at the expense of the physiological chain length CER NS with a C24 acyl chain (CER NS(C24)) impacts the microstructure and barrier function of a lipid model that mimicked certain characteristics of the SC lipid organization. The permeability and lipid organization of the model membranes were compared with that of a control model without CER NS(C16). The permeability increased significantly when ≥50% of CER NS(C24) was substituted with CER NS(C16). Employing biophysical techniques, we showed that the lipid packing density reduced with an increasing proportion of CER NS(C16). Substitution of 75% of CER NS(C24) by CER NS(C16) resulted in the formation of phase-separated lipid domains and alteration of the LPP structure. Using deuterium-labeled lipids enabled simultaneous characterization of the C24 and C16 acyl chains in the lipid models, providing insight into the mechanisms underlying the reduced skin barrier function in diseased skin.

| S-EPMC8389989 | biostudies-literature

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.

Project description: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.

| S-EPMC8303283 | biostudies-literature

Permeability Barrier and Microstructure of Skin Lipid Membrane Models of Impaired Glucosylceramide Processing.

Project description:Ceramide (Cer) release from glucosylceramides (GlcCer) is critical for the formation of the skin permeability barrier. Changes in β-glucocerebrosidase (GlcCer'ase) activity lead to diminished Cer, GlcCer accumulation and structural defects in SC lipid lamellae; however, the molecular basis for this impairment is not clear. We investigated impaired GlcCer-to-Cer processing in human Cer membranes to determine the physicochemical properties responsible for the barrier defects. Minor impairment (5-25%) of the Cer generation from GlcCer decreased the permeability of the model membrane to four markers and altered the membrane microstructure (studied by X-ray powder diffraction and infrared spectroscopy), in agreement with the effects of topical GlcCer in human skin. At these concentrations, the accumulation of GlcCer was a stronger contributor to this disturbance than the lack of human Cer. However, replacement of 50-100% human Cer by GlcCer led to the formation of a new lamellar phase and the maintenance of a rather good barrier to the four studied permeability markers. These findings suggest that the major cause of the impaired water permeability barrier in complete GlcCer'ase deficiency is not the accumulation of free GlcCer but other factors, possibly the retention of GlcCer bound in the corneocyte lipid envelope.

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Arrangement of Ceramides in the Skin: Sphingosine Chains Localize at a Single Position in Stratum Corneum Lipid Matrix Models.

Project description:Understanding the structure of the stratum corneum (SC) is essential to understand the skin barrier process. The long periodicity phase (LPP) is a unique trilayer lamellar structure located in the SC. Adjustments in the composition of the lipid matrix, as in many skin abnormalities, can have severe effects on the lipid organization and barrier function. Although the location of individual lipid subclasses has been identified, the lipid conformation at these locations remains uncertain. Contrast variation experiments via small-angle neutron diffraction were used to investigate the conformation of ceramide (CER) N-(tetracosanoyl)-sphingosine (NS) within both simplistic and porcine mimicking LPP models. To identify the lipid conformation of the twin chain CER NS, the chains were individually deuterated, and their scattering length profiles were calculated to identify their locations in the LPP unit cell. In the repeating trilayer unit of the LPP, the acyl chain of CER NS was located in the central and outer layers, while the sphingosine chain was located exclusively in the middle of the outer layers. Thus, for the CER NS with the acyl chain in the central layer, this demonstrates an extended conformation. Electron density distribution profiles identified that the lipid structure remains consistent regardless of the lipid's lateral packing phase, this may be partially due to the anchoring of the extended CER NS. The presented results provide a more detailed insight on the internal arrangement of the LPP lipids and how they are expected to be arranged in healthy skin.

| S-EPMC7498151 | biostudies-literature

Determining the structure of protein-bound ceramides, essential lipids for skin barrier function.

Project description:Protein-bound ceramides, specialized ceramides covalently bound to corneocyte surface proteins, are essential for skin permeability barrier function. However, their exact structure and target amino acid residues are unknown. Here, we found that epoxy-enone (EE) ceramides, precursors of protein-bound ceramides, as well as their synthetic analog, formed stable conjugates only with Cys among nucleophilic amino acids. NMR spectroscopy revealed that the β-carbon of the enone was attached by the thiol group of Cys via a Michael addition reaction. We confirmed the presence of Cys-bound EE ceramides in mouse epidermis by mass spectrometry analysis of protease-digested epidermis samples. EE ceramides were reversibly released from protein-bound ceramides via sulfoxide elimination. We found that protein-bound ceramides with reversible release properties accounted for approximately 60% of total protein-bound ceramides, indicating that Cys-bound EE ceramides are the predominant protein-bound ceramides. Our findings provide clues to the molecular mechanism of skin barrier formation by protein-bound ceramides.

| S-EPMC10641502 | biostudies-literature

Effect of sphingosine and phytosphingosine ceramide ratio on lipid arrangement and barrier function in skin lipid models.

Project description:The lipids in the uppermost layer of the skin, the stratum corneum (SC), play an important role in the skin barrier function. The three main subclasses in the SC lipid matrix are ceramides (CER), cholesterol, and free fatty acids. In inflammatory skin diseases, such as atopic dermatitis and psoriasis, the SC lipid composition is modulated compared to the composition in healthy SC. One of the main alterations is the molar ratio between the concentration of CER N-(tetracosanoyl)-sphingosine (CER NS) and CER N-(tetracosanoyl)-phytosphingosine (CER NP), which correlated with an impaired skin barrier function. In the present study, we investigated the impact of varying the CER NS:CER NP ratios on the lipid organization, lipid arrangement, and barrier functionality in SC lipid model systems. The results indicate that a higher CER NS:CER NP ratio as observed in diseased skin did not alter the lipid organization or lipid arrangement in the long periodicity phase encountered in SC. The trans-epidermal water loss, an indication of the barrier functionality, was significantly higher for the CER NS:CER NP 2:1 model (mimicking the ratio in inflammatory skin diseases) compared to the CER NS:CER NP 1:2 ratio (in healthy skin). These findings provide a more detailed insight into the lipid organization in both healthy and diseased skin and suggest that in vivo the molar ratio between CER NS:CER NP contributes to barrier impairment as well but might not be the main factor.

| S-EPMC10457584 | biostudies-literature

Topically Applied Ceramides Interact with the Stratum Corneum Lipid Matrix in Compromised Ex Vivo Skin.

Project description:PURPOSE:To determine whether formulations containing ceramides (including a ceramide with a long hydroxyl acyl chain linked to a linoleate, CER EOS) and fatty acids are able to repair the skin barrier by normalizing the lipid organization in stratum corneum (SC). METHODS:The formulations were applied on a skin barrier repair model consisting of ex vivo human skin from which SC was removed by stripping. The effect of formulations on the lipid organization and conformational ordering in the regenerated SC were analyzed using Fourier transform infrared spectroscopy and small angle X-ray diffraction. RESULTS:Application of the formulation containing only one ceramide on regenerating SC resulted in a higher fraction of lipids adopting an orthorhombic organization. A similar fraction of lipids forming an orthorhombic organization was observed after application of a formulation containing two ceramides and a fatty acid on regenerating SC. No effects on the lamellar lipid organization were observed. CONCLUSIONS:Application of a formulation containing either a single ceramide or two ceramides and a fatty acid on regenerating SC, resulted in a denser lateral lipid packing of the SC lipids in compromised skin. The strongest effect was observed after application of a formulation containing a single ceramide.

| S-EPMC5801391 | biostudies-literature

ZFP750 regulates skin lipid metabolism and cutaneous barrier

Project description:A life-essential function of the epidermis is to provide a physical barrier that prevents the loss of water and electrolytes. Essential mediators of this permeability barrier function include ceramides, cholesterol and very long chain fatty acids. Accordingly, their alteration may lead to distinct human conditions, including psoriasis or atopic dermatitis. Recently, a frameshift mutation in the human ZNF750 gene, that encodes for a zinc finger transcription factor, causing a seborrhea-like dermatitis with psoriasiform element, has brought ZNF750 as a key element for the maintenance of the epidermal tissue homeostasis. To clarify this hypothesis, with its underlying molecular mechanism, we generated a novel mouse knockout by deleting exon 2. Here, we show that genetic deletion of the mouse homolog ZFP750 results in loss of epidermal permeability barrier function. ZFP750-/- mice die shortly after birth, within 12 hours. In the stratum corneum of ZFP750-/- mice levels of ceramides, nonpolar lipids and intercellular lipid lamellae are significantly reduced. The alteration of the epidermal lipid homeostasis is directly linked to the transcriptional activity of ZFP750. Indeed, in addition to epidermal differentiation genes, ZFP750 directly and/or indirectly regulates the expression of nearly 50 crucial enzymes in the biosynthesis of ceramides, such as SPTLC1, DGAT2, SMPD3, ELOVL7 and DEGS2. Overall, our study identifies the transcription factor ZFP750 as a master regulator of lipid biosynthesis and epidermal homeostasis and may contribute to our understanding of the pathogenesis of several human skin diseases.

2023-05-03 | GSE220813 | GEO

Biophysical properties of novel 1-deoxy-(dihydro)ceramides occurring in mammalian cells.

Project description:Ceramides and dihydroceramides are N-acyl derivatives of sphingosine and sphinganine, respectively, which are the major sphingoid-base backbones of mammals. Recent studies have found that mammals, like certain other organisms, also produce 1-deoxy-(dihydro)ceramides (1-deoxyDHCers) that contain sphingoid bases lacking the 1-hydroxyl- or 1-hydroxymethyl- groups. The amounts of these compounds can be substantial-indeed, we have found comparable levels of 1-deoxyDHCers and ceramides in RAW 264.7 cells maintained in culture. The biophysical properties of 1-deoxyDHCers have not yet been reported, although these lipids might play important roles in normal cell regulation and in the pathology of diseases in which they are elevated, such as hereditary sensory autonomic neuropathies or diabetes. This study uses several approaches, including surface-pressure measurements, differential scanning calorimetry, and confocal microscopy, to study the behavior of 1-deoxyDHCers of different N-acyl-chain lengths and their interaction with sphingomyelin (SM). The thermotropic behaviors of 1-deoxyDHCers alone and in mixtures with SM are described, together with their interactions in monolayers and giant unilamellar vesicles. The gel-fluid transition temperatures of the pure compounds increase in the order 1-deoxyceramide < ceramide ≈ 1-deoxyDHCer < 1-(deoxymethyl)DHCer. In general, canonical ceramides are more miscible with SM in bilayers than are 1-deoxyceramides, and 1-(deoxymethyl)DHCers are the most hydrophobic among them, not even capable of forming monolayers at the air-water interface. Thus, these properties suggest that 1-deoxyDHCer can influence the properties of cellular membranes in ways that might affect biological function/malfunction.

| S-EPMC4269796 | biostudies-literature

Effects of omega-<i>O</i>-acylceramide structures and concentrations in healthy and diseased skin barrier lipid membrane models.

Project description:Ceramides (Cers) with ultralong (∼32-carbon) chains and ω-esterified linoleic acid, composing a subclass called omega-O-acylceramides (acylCers), are indispensable components of the skin barrier. Normal barriers typically contain acylCer concentrations of ∼10 mol%; diminished concentrations, along with altered or missing long periodicity lamellar phase (LPP), and increased permeability accompany an array of skin disorders, including atopic dermatitis, psoriasis, and ichthyoses. We developed model membranes to investigate the effects of the acylCer structure and concentration on skin lipid organization and permeability. The model membrane systems contained six to nine Cer subclasses as well as fatty acids, cholesterol, and cholesterol sulfate; acylCer content-namely, acylCers containing sphingosine (Cer EOS), dihydrosphingosine (Cer EOdS), and phytosphingosine (Cer EOP) ranged from zero to 30 mol%. Systems with normal physiologic concentrations of acylCer mixture mimicked the permeability and nanostructure of human skin lipids (with regard to LPP, chain order, and lateral packing). The models also showed that the sphingoid base in acylCer significantly affects the membrane architecture and permeability and that Cer EOP, notably, is a weaker barrier component than Cer EOS and Cer EOdS. Membranes with diminished or missing acylCers displayed some of the hallmarks of diseased skin lipid barriers (i.e., lack of LPP, less ordered lipids, less orthorhombic chain packing, and increased permeability). These results could inform the rational design of new and improved strategies for the barrier-targeted treatment of skin diseases.

| S-EPMC6997605 | biostudies-literature

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