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OCL
Volume 26, 2019
Lipids in the elderly: needs, nutrition and physiopathology / Les lipides pour les seniors : besoins, alimentation et physiopathologie
Article Number 17
Number of page(s) 7
DOI https://doi.org/10.1051/ocl/2019013
Published online 10 April 2019

© N. Jonca, Published by EDP Sciences, 2019

Licence Creative CommonsThis is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

1 Introduction

The epidermis is a stratified epithelium consisting mainly of keratinocytes (Fig. 1). These cells differentiate throughout their migration from the basal layer towards the external surface of the skin. At the latest stage, they undergo cornification, a programmed cell death leading to the transformation of granular keratinocytes, the last living cells in the program of keratinocyte terminal differentiation, into corneocyte. Stacking of the corneocytes forms the stratum corneum, the outermost layer of the epidermis. The stratum corneum is essential for the main function of the epidermis, the barrier function, vital for the organism. It mainly fulfils the permeability barrier function by dampening transepidermal loss of water and electrolytes and by preventing entry of toxic or pathogenic agents. An impaired epidermal barrier is associated with numerous skin diseases like atopic dermatitis, psoriasis or rare genodermatoses such as ichthyoses (Castiel-Higounenc et al., 2004; van Smeden et al., 2014). Elderly skin is typically thin and fragile, with increasing susceptibility to bruising and impaired wound healing (Gilchrest, 1996). The stratum corneum and more particularly the stratum corneum lipid structures are expected to undergo significant changes during the course of ageing. However, this has been little studied in comparison to other skin compartment like the dermis.

thumbnail Fig. 1

Histology of normal human epidermis (hemalun-eosin staining).

2 Epidermal barrier and stratum corneum lipids: importance of ω-O-acylceramides

Lipids play an important role in the epidermal permeability barrier function. Human stratum corneum lipids consist of 50% ceramides, 25% cholesterol, 10–15% free fatty acids (predominantly long-chain and saturated) and 5% of other various lipids. Sebaceous glands produce triglycerides, squalene, waxes, cholesterol and free fatty acids that form a hydro-lipid film at the surface of the skin while most components of the lipid-rich extracellular matrix of the stratum corneum are produced by the underlying living keratinocytes from the granular layer. Precursors of these stratum corneum lipids, such as glucosyl(acyl)ceramides, phospholipids and sphingomyelin, are stored in the tubulo-vesicular secretory organelles called lamellar bodies. At the stratum granulosum/stratum corneum interface, these precursors are released and processed into mature products that assemble into continuous hydrophobic lamellar lipid structures surrounding the corneocytes, the lamellae, or are crosslinked to the cornified envelope of corneocytes to form the cornified lipid envelope (Menon et al., 2012).

Ceramides are sphingolipids resulting from the combination of a fatty acid and a sphingoid base via an amine link. They are the major lipid species in the stratum corneum, where they present a high degree of complexity linked to an important molecular heterogeneity. The sphingoid moiety can be sphingosine (S), dihydrosphingosine (D), phytosphingosine (P) or 6-hydroxy-sphingosine (H). The diversity of epidermal ceramides is additionally enhanced by the huge fatty acid moiety linked in amine position which can be non-hydroxy (N), α-hydroxy (A) or ester linked ω-hydroxy (EO) (Tab. 1). There is a high level of ω-hydroxyceramide with ultra-long carbon chain (C28-C38). Two major distinctive classes of ceramides derive from esterification of the ω-hydroxyl group: ω-fatty acid (predominantly linoleic acid) esterified ultra-long chain-ceramides, and protein bound ceramides due to esterification with glutamate side chains of cornified envelope proteins (Jennemann et al., 2012; Rabionet et al., 2014). These two ceramide species are specific to epidermis and are essential for lipid-matrix organization into lamellae and formation of the corneocyte lipid envelope (Menon et al., 2012).

The specific importance of epidermal ceramides has been assigned definitively to their role in maintaining epidermal barrier homeostasis. Numerous enzymes and molecular actors are necessary for the synthesis, transport, secretion and extracellular maturation of all major epidermal ceramides. Most of them have been recently uncovered. In short, esterified and protein-bound ceramides (i.e. ceramides forming the cornified lipid envelope) require starts in late stratum spinosum/early stratum granulosum with the synthesis of ω-hydroxylated ultra-long fatty acids (C28-C38) at the endoplasmic reticulum, which requires the fatty acid elongase ELOVL4 (Li et al., 2007) and the hydroxylase CYP4F22 (Ohno et al., 2015). After activation, which involves SLC27A4/FATP4 (Herrmann et al., 2005; Moulson et al., 2007), a specialized ceramide synthase, CERS3, condenses the ultra-long ω-hydroxy-fatty acids with sphingoid bases to form ω-hydroxy-(dihydro)ceramides (Jennemann et al., 2012). The transacylase PNPLA1, most probably enhanced by the co-factor ABHD5, allows ω-esterification of ceramides with linoleic acid released from triglycerides (Ohno et al., 2017, 2018). The resulting ω-esterified ceramides then require transport to the Golgi where glucosylation involves the ubiquitously expressed glycosylceramide synthase UGGT to form ω-esterified glucosylceramides, a polar preform of the barrier ceramide (Jennemann et al., 2007). Omega-esterified (glucosyl) ceramides then are packed together with polar precursors of other barrier lipids into lamellar bodies, which requires the ABC transporter ABCA12 (Smyth et al., 2008). Fusion of lamellar bodies with the plasma membrane by the SNARE-complex may involve the isoform SNAP29 (Schiller et al., 2016). Most of the secreted barrier lipids will form the extracellular lipid lamellae, but some are trans-esterified to proteins of the cornified envelope to form the cornified lipid envelope (Breiden and Sandhoff, 2014). This trans-esterification involves initial oxidation of the ω-bound linoleic acid by 12R-LOX and eLOX3, and finally transglutaminase TGase1 transfers ω-hydroxy-glucosylceramides onto proteins of the cornified envelope (Krieg et al., 2013). Protein-bound glucosylceramides are processed by glucosylceramidase, an acidic ceramidase, with the help of activator proteins to form protein-bound ω-hydroxy-ceramides and later protein bound ω-hydroxy-fatty acids (Breiden and Sandhoff, 2014; Rabionet et al., 2014) (Fig. 2).

Table 1

Structure and correspondent nomenclatures of human epidermal ceramides.

thumbnail Fig. 2 Omega-O-acylceramide is an epidermis specific sphingolipid with a crucial role for epidermal barrier function.

Diagram showing the synthesis and transport of omega-O-acylceramide in the granular keratinocyte, their secretion at the interface stratum granulosum/stratum corneum and their extracellular processing and assembling into the stratum corneum lipid structures (lamellae and cornified lipid envelope) (see text for details).

3 Omega-O-acylceramides and pathophysiological study of ichthyoses: example of the elucidation of PNPLA1 biological role

Numerous inherited skin diseases directly result from abnormalities in sphingolipids. Identification and characterization of the corresponding genes, as well as the study of the corresponding KO mouse models, largely contributed to a better knowledge of fundamental aspects of ceramide metabolism (Elias et al., 2008; Borodzicz et al., 2016). This was particularly the case with the pathophysiological study of Autosomal Recessive Congenital Ichthyoses (ARCI), a subgroup of rare monogenic skin diseases due to mutation of genes involved in cornification.

At birth many ARCI patients are “collodion babies”, a descriptive term for infant born encased in a tight shiny skin that resembles plastic wrap. Later, the skin phenotype consists in generalized scaling and variable erythroderma, with a wide spectrum of clinical presentations from lamellar ichthyosis to congenital ichthyosiform erythroderma. To date, mutations associated with ARCI have been described in 10 genes: ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, NIPAL4, PNPLA1, SDR9C7, SULT2B1 and TGM1. Some of them have been addressed in many works which demonstrated their involvement in stratum corneum lipid metabolism. Recently, our group as well as others showed that PNPLA1 was a key player in the formation of ω-esterified ceramides (Grond et al., 2017; Hirabayashi et al., 2017; Ohno et al., 2017; Pichery et al., 2017).

Patatin-like phospholipase domain containing 1 (PNPLA1) is one of the 9 members of the PNPLA family, characterized by a highly conserved “patatin” domain. These proteins have diverse lipolytic and acyltransferase activities and play a key role in the lipid metabolism (Wilson et al., 2006; Kienesberger et al., 2009). PNPLA1 was the less characterized member of this family. Interest in the biological function of this protein was enhanced by the recent identification of PNPLA1 gene as an ARCI-associated gene, originally in a spontaneous mutant dog model then in patients affected by ARCI for which no mutation in other already known ARCI-causing gene was detected (Grall et al., 2012). However, the enzymatic function of PNPLA1 remained unknown. In human, the protein is expressed in the epidermis, predominantly in the granular layer (Toulza et al., 2007; Grall et al., 2012). The only functional data concerning PNPLA1 arose from the work of Grall and coworkers. Their analyses of triglyceride hydrolase activity and [14C]-linoleic acid incorporation of normal and PNPLA1-deficient cultured human keratinocytes indicated that PNPLA1 had a role in the metabolism of glycerophospholipid rather than neutral lipids (Grall et al., 2012). Thus, deciphering the biological function of PNPLA1 could allow understanding its physiological role in the epidermis and its pathophysiological implication in ARCI.

In the lab, we searched for PNPLA1 mutations in patients suffering from ARCI from our biological collection. Among 105 patients analyzed, 5 novel PNPLA1 mutations were identified in 5 patients from 3 non-consanguineous Caucasian families. Four of these mutations corresponded to amino acid substitution in the highly conserved patatin domain and the fifth was a frameshift with a premature terminal codon that can be predicted to result either in mRNA decay or in the synthesis of a truncated protein. Thus, all these newly identified mutations were strongly suspected to affect the biological function of the protein. In order to better understand the function of PNPLA1 in the epidermis, we developed Pnpla1 knockout (KO) mice. Pnpla1 deficiency in mice led to neonatal lethality. Pnpla1 KO E18.5 embryos and newborns had a thick, taut and shiny skin with a shellacked appearance that led to reduced mobility and thus failure to suckle maternal milk. This “collodion-like” appearance was strongly evocative of the collodion baby observed in humans. Histological examination of the skin revealed an increased number of epidermal living layers (acanthosis) and a thick, compact stratum corneum, consistent with proliferation/differentiation disturbance. This phenotype was associated with impairment in the outside-in and inside-out permeability barrier function. Pnpla1-deficient mice lethality was most probably due to severe dehydration caused by both an inability to feed and epidermal barrier impairment. Similar lethal phenotypes have also been reported in mice invalidated for other genes causing ARCI (Matsuki et al., 1998; Epp et al., 2007; Jennemann et al., 2012; Krieg et al., 2013).

Pnpla1-deficient murine skin showed an important alteration in epidermal lipid composition and organization. Ultrastructural analyses of the KO skin by transmission electron microscopy showed an impaired organization of the extracellular lipid matrix in the stratum corneum. Indeed, the typical arrangement in lamellae was observed only in wild-type mice. Moreover, analyses of cornified fluorescent-labelled envelopes showed that when Pnpla1 was absent, cornified envelopes are mainly composed of crosslinked proteins with an obvious defect in lipid coverage (i.e. quasi-absence of cornified lipid envelope). Finally, liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) revealed that Pnpla1-deficient mice had a modified sphingolipid profile. Quantification of different species of ceramides in the mutant epidermis highlighted a drastic reduction in ω-esterified ceramides with a concomitant accumulation of their metabolic precursors, ω-hydroxyceramides. In accordance with the reduced level of esterified ceramides, we also observed a drastic reduction of their derivatives, the ceramides crosslinked to the cornified envelope, relevant with the impaired lipid coverage observed by fluorescence microscopy. These data obtained in mice were confirmed on patients suffering from ARCI. We evidenced in PNPLA1-mutated patients an alteration of the cornified lipid envelope. Moreover, PNPLA1 mutations resulted in an important decrease in stratum corneum esterified ceramides accompanied by an accumulation of its precursors.

Altogether, these results clearly showed that PNPLA1/Pnpla1 deficiency provoked a blockade in ω-esterified ceramide synthesis. Pnpla1-deficient mice were developed and analysed by two other groups that reported very similar and concordant results (Grond et al., 2017; Hirabayashi et al., 2017). Furthermore, the work of Kihara’s group allowed demonstrating the enzymatic activity of PNPLA1. Indeed, the experiments they performed in vitro or using transfected cell models demonstrated that PNPLA1 was able to transfer linoleic acid from triglyceride to ω-hydroxyceramides (Ohno et al., 2017). In the end, these studies demonstrated that PNPLA1 is a transacylase essential for the synthesis of ω-esterified ceramides.

4 Ceramides and skin ageing

Skin changes constitute the first obvious evidence of aging, a complex and multifactorial biological process affecting the whole body. Skin aging is influenced by several factors including genetics, environmental exposure (UV radiation, smoke, pollution…), hormonal changes and metabolic process. These intrinsic and environmental factors gradually make the skin thin, translucent, and more susceptible to trauma and bruise. Aged skin also presents marbled pigmentation, aged spots, loss of elasticity and wrinkles (Gilchrest, 1996).

Histologically, one of the most prominent changes with intrinsic aging is flattening of the dermal-epidermal junction, making it less resistant to shearing forces, as well as decreased thickness of the dermis and the epidermis. Concerning resident cells of the skin other than keratinocytes, a reduced number of melanocytes and Langerhans cells (the epidermal “sentinel” immune cells) have also been described. Comparatively to the dermis and the living layers of the epidermis, little histological changes appear in the stratum corneum of aged skin in comparison to young skin. Notably, it has a virtually normal thickness and basket-weave appearance. Age-dependent functional changes in the stratum corneum have been assessed by measuring different parameters like transcutaneous water loss (transepidermal water loss, TEWL), stratum corneum hydration or skin-surface pH. Some variations in one or more of these parameters were detected in aged skin in comparison to young skin of healthy male and female groups of volunteers, but globally the functionality of the stratum corneum appeared little or non-affected (Leveque et al., 1984; Ghadially et al., 1995; Tagami, 2008; Luebberding et al., 2013, 2014; Boireau-Adamezyk et al., 2014). However, when the barrier was experimentally perturbed, for instance with either acetone or tape stripping, it recovered more slowly in aged than in young human subjects (Ghadially et al., 1995). Moreover, it is well documented that aged skin is prone to develop altered drug permeability, increased susceptibility to irritants, contact dermatitis and severe xerosis. Thus the stratum corneum barrier function appears more “fragile” in elderly. Lipids and more particularly ceramide deficiency may account, at least in part, for this dysfunction of the stratum corneum associated with ageing.

A detailed analysis of the effect of aging on the lipid structures in the stratum corneum was performed by the group of P. Elias (Ghadially et al., 1995). They examined by transmission electron microscopy the lipid lamellae and the cornified lipid envelope of young vs. aged skin. In both aged human and mouse epidermis they observed a normal number of lamellar bodies in the granular keratinocytes cytosol, with normal internal structure. However, a paucity of secreted lamellar body contents was present at the stratum granulosum/stratum corneum interface. Moreover, the stratum corneum interstices contained focal domains that were either depleted or virtually devoid of lamellae. This study was completed by the analysis of lipid content which showed that the quantity of lipids in aged murine stratum corneum was globally reduced (∼30%), without exhibiting any specific abnormality in species distribution or fatty acid composition (Ghadially et al., 1995). Significantly decreased levels of all major lipid species, in particular ceramides, with increasing age, were also reported in human (Rogers et al., 1996).

Hence, treatments able to restore skin-ceramide levels and lipid organization in the stratum corneum could improve the epidermal barrier function in aged skin. For some years now many studies have been conducted to identify such treatments. Besides clinical trials performed on aged vs. young subjects (Seyfarth et al., 2011; Danby et al., 2016; Chang et al., 2018), one can also find interesting information from studies done on patients with skin diseases characterized by a perturbation of stratum corneum lipids and a defective barrier, like atopic dermatitis, psoriasis or ichthyoses (Lowe et al., 2012; Liu et al., 2015; Sahle et al., 2015), as well as studies using animal or in vitro models (Di Marzio et al., 2008; Moner et al., 2018; Popa et al., 2018).

Different strategies were developed in order to improve skin-ceramide levels. One consisted in direct replenishment of the missing lipids or their analogues. Several studies reported positive effects of topically applied preparations containing ceramides on skin barrier function (Kucharekova et al., 2002; Lowe et al., 2012; Liu et al., 2015; Sahle et al., 2015). Importantly, it seems that the therapeutic ceramide may not be applied alone but in combination with other lipids in order to maintain the ratio between the three major lipid components of the stratum corneum. Indeed, partial lipid compositions may result in abnormal lamellar bodies’ contents and hence may interfere with the formation of lamellae and cornified lipid envelope. The vehicle used to penetrate the stratum corneum is also important. Efforts are still done in the development of technologies with the aim of highly efficient delivery of the product. For instance, sphingomyelin-based liposomes and lamellar body mimetic system have recently been proposed (Itaya and Tokudome, 2016; Moner et al., 2016). Efficiency of topically applied substitutive lipid mixture may also differ regarding the nature of the topically applied ceramide. Different sources of therapeutic lipids have been proposed, including synthetic or animal-based ceramides as well as plant-derived ceramides (Tessema et al., 2017). Sometimes, therapeutic lipids were administered by oral dietary supplement. Although some clinical studies reported skin-moisturizing and skin barrier recovery effects of such dietary supplement, the fate of the ingested ceramide and the mechanisms underlying skin barrier improvement are still obscure (Tessema et al., 2017).

Another approach is to facilitate the production of the lipids in vivo. For instance, the administration of agents such as nicotinamide, ascorbic acid and its derivatives, or ursolic acid, a plant-derived triterpenoid, was found to effectively increase the synthesis of epidermal ceramides (Tanno et al., 2000; Yarosh et al., 2000; Katsuyama et al., 2017). Furthermore, the age-dependent increase of pH in the stratum corneum is known to have an impact on the activity of acidic-dependent lipid hydrolases involved in ceramide processing (e.g. β-glucocerebrosidase, sphingomyelinase). It has been shown that re-acidification of the stratum corneum with lacto bionic acid accelerated barrier recovery in old individual and led to increased formation of fully processed lamellae (Choi et al., 2007). In another study, researchers showed that topical application of bacterial sphingomyelinase from Streptococcus thermophilus increased skin-ceramide levels, improved the lipid barrier and augmented a resistance against ageing-associated xerosis in aged subjects (Di Marzio et al., 2008).

5 Conclusion

Stratum corneum lipids, and more particularly ω-O-acylceramides, play a crucial role in the epidermal barrier function. They are mainly produced by the differentiating living keratinocytes beneath the stratum corneum, undergo extracellular maturation in the lower stratum corneum to finally form extracellular lipid matrix lamellae and cornified lipid envelopes, the two essential lipid structures of the stratum corneum. Clarifying the role of the enzyme PNPLA1, which gene is mutated in some forms of congenital ichthyoses, is a further illustration emphasizing the crucial role of ω-O-acylceramides in the epidermal barrier function. Perturbation of the lipid organization in the stratum corneum is associated with skin conditions of impaired epidermal barrier, including numerous skin diseases (atopic dermatitis, psoriasis, ichthyoses), as well as aged skin in which the permeability barrier is more “fragile”. Age-dependent ceramide deficiency contributes to skin fragility in elderly. Restoration of skin-ceramide levels is part of treatments under development for combating the effects of skin aging. Many in vitro, animal and clinical studies are conduced to this end with encouraging and positive results. Continuation of those efforts and further experiments are needed to improve such treatments and better understand the underlying molecular mechanisms of lipid barrier restoration.

Conflicts of interest

The author declares that she has no conflicts of interest in relation to this article.

Acknowledgements

The author wishes to thank the staff of the lab “Epithelial Differentiation and Rheumatoid Autoimmunity” and more particularly Mélanie Pichery who was heavily involved in the work on PNPLA1. N.J. gratefully acknowledges support for the research project on PNPLA1 provided by PHENOMIN and the Société Française de Dermatologie.

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Cite this article as: Jonca N. 2019. Ceramides metabolism and impaired epidermal barrier in cutaneous diseases and skin aging: focus on the role of the enzyme PNPLA1 in the synthesis of ω-O-acylceramides and its pathophysiological involvement in some forms of congenital ichthyoses. OCL 26: 17.

All Tables

Table 1

Structure and correspondent nomenclatures of human epidermal ceramides.

In the text

All Figures

thumbnail Fig. 1

Histology of normal human epidermis (hemalun-eosin staining).
In the text
thumbnail Fig. 2 Omega-O-acylceramide is an epidermis specific sphingolipid with a crucial role for epidermal barrier function.

Diagram showing the synthesis and transport of omega-O-acylceramide in the granular keratinocyte, their secretion at the interface stratum granulosum/stratum corneum and their extracellular processing and assembling into the stratum corneum lipid structures (lamellae and cornified lipid envelope) (see text for details).
In the text

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