International Journal of Cosmetic Science, 2017, 39, 366–372 doi: 10.1111/ics.

12399

Review Article
The chemistry, function and (patho)physiology of stratum corneum
barrier ceramides

D. J. Moore* and A. V. Rawlings†

*GSK Consumer Healthcare, Skin Health R&D, 184 Liberty Corner Road, Warren, NJ 07059, USA and †AVR Consulting Ltd, 26 Shavington Way,
Kingsmead, Northwich, Cheshire CW9 8FH, UK

Received 22 January 2017, Accepted 19 March 2017

Keywords: barrier, ceramides, lipid organization, stratum corneum, xerosis

Abstract la phytosphingosine et un taux
elev
e de lipides / prot
eines du SC,

Research on understanding of the chemistry, function and (patho)-
physiology of stratum corneum (SC) lipids and especially ceramides
has evolved over the last two decades. This has been made success-
ful through the application of separation techniques that have
become increasingly more sophisticated, and it has become increas-
ingly evident that our understanding of these molecules remains in
its infancy. Thirteen classes of ceramides with over 300 and possi-
bly up to 1000 distinct ceramide species have been identified sug-
gesting an exquisitely subtle relationship between the types of
ceramides and physical and chemical behaviour. Nevertheless,
research has demonstrated the importance of the correct SC lipid
lamellar architecture with conformationally-ordered lipid bilayers,
the presence of long-chain ceramides, as either free or covalently
bound lipids, greater quantities of phytosphingosine-containing cer-
amides and a high SC lipid/protein ratio is essential for optimal
barrier function. These features are known to change in a variety
of physiological and pathophysiological conditions. Clearly, there is
more to be learned but as we further decipher the complexity of SC
lipids and understand their individual roles in the SC, we will learn
how to better treat the disorders of cornification.
Re
sume

Des recherches sur la compr
ehension de la chimie, de la fonction et
de la (patho)physiologie des lipides du stratum corneum (SC) et en
particulier des c
eramides ont
evolu
e au cours des deux dernieres
d
ecennies. Cela a
et
e couronn
e de succes gr^ace a l’application de
techniques de s
eparation qui sont devenues de plus en plus sophis-
tiqu
ees et il est devenu de plus en plus
evident que notre
compr
ehension de ces mol
ecules reste a  ses d
ebuts. Treize classes
de c
eramides avec plus de 300 et
eventuellement jusqu’a 1000
especes distinctes de c
eramide ont
et
e identifi
ees, ce qui suggere
une relation tres subtile entre les types de c
eramides et le comporte-
ment physicochimique. N
eanmoins, la recherche a d
emontr
e l’im-
portance de l’exactitude de l’architecture lamellaire lipidique du SC
avec la conformation en bicouches lipidiques, de la pr
esence de
c
eramides a longue cha^ıne, qu’ils soient libres ou li
es de facßon
covalante, de la plus grandes quantit
es de c
eramides contenant de
Correspondence: Professor Anthony Rawlings, AVR Consulting Ltd, 26
Shavington Way, Northwich, Cheshire CW9 8FH, UK. Tel.:
01606330235; e-mail: TonyRawlings@avrconsultingltd.com
est essentiel pour une fonction de barriere optimale. Ces caract
eris-
tiques sont connues pour varier suivant les conditions physiologi-
ques et pathophysiologiques. De toute
evidence, il y a plus a 
apprendre, mais a  mesure que nous d
echiffrions davantage la com-
plexit
e des lipides du SC et que nous comprenons leurs r^ oles indivi-
duels dans le SC, nous apprendrons a mieux traiter les troubles de
la k
eratinisation.
Introduction
To protect against the damaging effect of the environment the
skin’s epidermis has evolved to generate and maintain a stratum
corneum (SC), which composed of cellular and macromolecular
components that provide the required structure, hydration, plasti-
cization and barrier to water loss [1]. The SC consists of three basic
components: natural moisturizing factor (NMF)-laden and lipid-
bound corneocytes (terminally differentiated keratinocytes), cor-
neodesmosomes (proteinaceous rivets holding corneocytes together)
and lipids. A widely employed, if over-simplified, analogy of gross
SC structural organization is that of a brick and mortar wall [1]. In
this model, the corneocyte ‘bricks’ occupy most of the volume of
the SC wall and are surrounded by a lipid ‘mortar’. Corneodesmo-
somes interlock the bricks to ensure maximum structural integrity.
Equally, the size and morphology of the corneocytes, which dictates
the tortuosity of the SC, and the total thickness of the SC also influ-
ence SC barrier function, whereas filaggrin and its degraded com-
ponents compact keratin and provide hydration and plasticity,
respectively[1].
The lipid continuous phase of the barrier accounts for approxi-
mately 20% of the SC’s volume and about 15% of its dry weight
[2]. The hydrophobic intercellular lipid bilayers and covalently
bound lipids (CBL) of the SC provide a barrier for the diffusion of
water through the SC. The SC’s lamellar bilayer organization was
first observed clearly using electron microscopy [3]. Consistent with
the ‘mortar’ analogy, however, there is good evidence to indicate
that the lipids also contribute to the intercellular cement, which
helps to maintain the integrity of the tissue [1].
The major lipid species of the SC are ceramides (about 50%),
fatty acids (10–20%) and cholesterol (25%) [4]. In addition, there
are small amounts of cholesterol esters and cholesterol sulphate
[5]. These components fuse together to form the continuous

366 © 2017 Society of Cosmetic Scientists and the Soci
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Stratum corneum ceramides
lamellar bilayers characteristic of the SC. This study will review the
most recent developments in our understanding of the chemistry,
function and pathophysiology of ceramides, the major polar species
from which the lamellar structures of the SC are organized.
The structure of stratum corneum ceramides
Our understanding of the heterogeneity of SC ceramides continues
to increase in parallel with the development of new highly sensitive
analytical methodologies for their detection and measurement [6,
7]. The previously described studies by Masukawa and colleagues
employing normal-phase liquid chromatography (NPLC) connected
to electro-spray ionization-mass spectrometry (ESI-MS), which pro-
vided new quantitative insights into the diversity of ceramide
classes and species in human stratum corneum [8, 9] have been
further advanced by several groups in the Netherlands, Belgium
and Germany [10–12].
Fifteen classes of free ceramides (Fig. 1a; non-corneocyte-bound)
have been identified including the newly identified and classified
1-O-acylceramides, which contain long acyl chains in both the
N- and O-positions [12]. In addition, three classes of covalently
bound ceramides (Fig. 1) are known [13].
The chemical structures of the fifteen free ceramides classes are
labelled according to the nomenclature system that was first sug-
gested some years ago [14] and is based on the molecular struc-
tures corresponding to the sphingoid base chains sphingosine (S),
6-hydroxy sphingosine (H), dihydrosphingosine (DS), phytosphin-
gosine (P), dihydroxy sphinganine (T); and the fatty acid chains
alpha-hydroxy acid (A), non-hydroxy fatty acid (N) and omega-
hydroxy fatty acid (O). The complete molecule is designated by ‘ce-
ramide-acid-base’, that is, the acid chain abbreviation precedes the
base chain. In the case of ceramides esterified with an additional
fatty acid, the letter E precedes the base and fatty acid chains. For
ceramides covalently bonded to the corneocyte protein envelope via
the omega-hydroxy fatty acid the letter P precedes the base and
fatty acid chain letters. For example, a 6-hydroxy sphingosine with
an alpha-hydroxy fatty acid chain is denoted as CER[AH]. The free
ceramide classes possible from the above combinations of acid and
bases are shown in Fig. 1a, whereas the relative concentration of
each class is listed in Table I based upon the recent work of t’Kindt
et al. [11]. It should be noted that much of the older skin ceramide
literature uses nomenclature that is inconsistent with more recent
understanding and nomenclature.
Human SC ceramide base chains range from 18 to 22 car-
bons in length [15]. For the non-hydroxy fatty acid ceramides
the amide linked fatty acid chains range from 16 to 32 carbons
in length with the major chain species being either 24 or 26
carbons. For the omega-hydroxy ceramides, the fatty acid chains
range from 30 to 34 carbons in length with linoleic acid
(C18:2) esterified to the omega-hydroxy group. The pioneering
analytical work of Masukawa and colleagues in evaluating SC
ceramides was in general agreement [8, 9] with the above and
has been significantly added to by the very recent work cited
above [10–12]. Furthermore, the identification of several odd
numbered fatty acid chains in SC ceramides has been confirmed
in these recent studies [16, 17]. Table II lists the relative distri-
bution of total ceramide carbon atoms as recently described by
van Smeden and colleagues [10]. Using NPLC-ESI-MS methods
over 300 ceramide species had been to which approximately
100 new species are added together with the identification of
the 1-O-acylceramides [9, 10, 12]. Further improvements in
© 2017 Society of Cosmetic Scientists and the Soci
et
e Francßaise de Cosm
etologie
International Journal of Cosmetic Science, 39, 366–372
D. J. Moore and A. V. Rawlings
these techniques appear set to herald the dawn of epidermal sph-
ingolipid and ceramide lipidomics.
Certain ceramides are covalently bonded to the outside aspect of
the corneocyte protein envelope via the formation of ester linkages
between hydroxyl groups on the ceramides and carbonyls of the
beta-sheet proteins of the cornified cell envelope [18]. Three cova-
lently bound ceramides have been identified one consisting of a
sphinganine base (C17-22), another a phytosphingosine base and
the third a dihydrosphingosine base all linked to omega-hydroxya-
cid; designated CER[POS], CER[POP] and CER [POdH], respectively
[13]. All the omega-hydroxyceramides of corneocyte lipid envelopes
are attached to proteins through their omega-hydroxyl groups
[19]. It has been determined that there is enough lipid covalently
attached to the corneocyte protein envelope to form a complete
lipid monolayer over the surface of each cell [2]. The very long
chains of the envelope ceramides lipids will be conformationally
ordered thereby forming a water barrier around each corneocyte
[18]. A proposed critical function of this layer is to cover the cor-
neocytes with a lipophilic coating, which acts as a template or scaf-
fold to direct the assembly of the extruded lamellar body lipids into
lamellar bilayers [2]. It has also been proposed that the corneocyte
envelope may function as a semipermeable membrane permitting
water transport but preventing the transport of natural moisturiz-
ing factor (NMF) out of corneocytes [1].
Lipid organization in the stratum corneum
The continuous lamellar bilayer of most biological membranes con-
sists of lipids predominantly in the liquid crystalline (La) state. In
this state, the lipid chains have considerable intramolecular confor-
mational disorder and lateral mobility within the plane of the
plane. Aliphatic liquid crystal forming lipids can undergo reversible
transitions between the lamellar gel phase (Lb) and the lamellar La
phase. In the Lb phase, hydrocarbon chains are in a fully extended
all-trans conformation, and the chains are packed in a 2-dimen-
sional hexagonal array that allows for some limited rotational free-
dom along the axes of the chains. Saturated long-chain lipids can
also pack in lamellar bilayers in which the chains are packed in a
2-dimensional orthorhombic array. In this phase, the chains are
conformationally ordered, packed in a very tight crystalline array,
and have no rotational freedom [20].
The complexity of the lipid composition of the SC, its unusual
composition and unique physical properties suggest the likelihood
of a unique molecular organization. The very long carbon chain
lengths of SC ceramides and free fatty acids along with the small
polar head groups of these lipids determine the unusual and highly
specialized physical properties of the SC lipid lamellae. A variety of
biophysical techniques including nuclear magnetic resonance
(NMR), wide-angle and small-angle X-ray diffraction, differential
scanning calorimetry (DSC), Fourier transform infrared (FTIR) spec-
troscopy and Raman spectroscopy have presented a detailed molec-
ular level picture of lipid organization in the SC.
A variety of published reports have established that the hydro-
carbon chains of SC lipids are highly ordered. McIntosh and co-
workers, in X-ray studies of mixtures containing ceramides, fatty
acids and cholesterol, observed ordered gel phase lipids at 25 mole
% cholesterol, which did not depend on the amount of water pre-
sent, or on the presence of protein [21]. The repeat unit of 130
angstroms in these studies was postulated to arise from two bilay-
ers. In early wide-angle X-ray studies of murine SC, White and col-
leagues reported the presence of some crystalline orthorhombic
367
Stratum corneum ceramides D. J. Moore and A. V. Rawlings

(a)

(b)

Figure 1 Structures of the major free (a) and bound (b) ceramide classes of human SC.

lipids at physiological temperature [22]. Seminal studies by Bouw- acid models of SC [23–25]. In addition, Bouwstra and colleagues
stra and colleagues utilizing X-ray diffraction and electron diffrac- have demonstrated the importance of CER[EOS] in producing the
tion techniques demonstrated the presence of orthorhombic phase intermolecular organization necessary for healthy skin barrier func-
lipids in isolated human SC as well as ceramide/cholesterol/fatty tion [26]. As the above mentioned studies many further studies

368 © 2017 Society of Cosmetic Scientists and the Soci
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International Journal of Cosmetic Science, 39, 366–372
Stratum corneum ceramides D. J. Moore and A. V. Rawlings

Table I Approximate percentage of major free ceramide species to total SC measurements have been repeatedly confirmed. Iwai et al.,
ceramide pool in the stratum corneum. reported that the barrier consists of fully extended ceramides with
cholesterol molecules associated with the sphingoid moiety [28].
Ceramide nomenclature Percent of total ceramide
Variations in SC ceramide levels
Ceramide [NS] 7.4 In this section, we review specifically the changes in ceramide com-
Ceramide [NDS] 9.8 position characteristic of various skin disorders ranging from com-
Ceramide [NP] 22.1
mon xerotic skin barrier problems to skin diseases. However, not
Ceramide [NH] 14.5
Ceramide [NT] 1.7 all ceramide subspecies have been investigated in disease states as
Ceramide [AS] 9.6 their structures were only recently identified. The lipidomics of the
Ceramide [ADS] 1.6 skin barrier (particularly SC ceramides) and the underlying links
Ceramide [AP] 8.8 with skin diseases is still in its infancy.
Ceramide [AH] 10.8
Ceramide [EOS] 6.5
Ceramide [EOP] 1.1 Body site variation
Ceramide [EOH] 4.3
Ceramide [EODS] 0.4 Before discussing skin conditions, it is important to recognize that
Ceramide [1-O-ENS] <2.0 there are differences in SC lipids on different body sites. Compar-
Ceramide [1-O-EAS] <2.0 ing mass of lipid to protein, Rogers et al. [29] found that hand SC
had greater quantities of barrier lipids to leg SC but that both
had dramatically elevated levels of SC barrier lipids compared to
the face. Equally, Watkinson et al. [30] also found increased lipids
Table II The relative distribution of total carbon atoms (both chains) in the in axillary SC with less percentage of ceramides and specifically
ceramides of human stratum corneum. Table lists only species contributing less CER [NP] but greater [AH] compared with forearm SC. Masu-
>2%, it is noted that many minor species exist and have been quantified. kawa et al. also compared cheek and forearm body sites and
found decreased levels of CER [NP], [NH], [NDS], [EOS], [EOP]
Ceramide chain length (total carbon atoms) Percent abundance
and [EOH] on the cheek and increased levels of [NS]. In addition,
the total carbon of CER [NS] was generally shorter on the cheek
with carbon chain lengths of 33–37 not being present in forearm
34 2 SC [8, 9]. Ishikawa et al. [31] further examined the ceramide
40 3 composition for a variety of body sites and observed that the skin
41 4
on the lower legs, forearm, head upper arm, buttock and scalp
42 9
43 6 has higher total ceramides compared with that of the palm, fin-
44 13 ger, lip, back of the hand and cheek. The palm, finger, lip and
45 6 cheek showed a lower percentage of CER[NP], CER[EOS], CER
46 14 [EOH] and CER[EOP] and a higher percentage of CER[NS] and
47 5
CER[AS]. The skin on the scalp had the highest percentage of
48 10
49 3
CER[NdS] and CER[EOP], and the skin on the palm had the low-
50 5 est percentage of CER[EOS], CER[EOH] and CER[EOP]. Equally, the
51 2 average carbon numbers of CER[NS] were shorter on the lip,
52 2 palm, cheek and fingers compared with other body sites. C34-CER
66 2 [NS] was higher on the scalp, forehead, cheek and lip compared
68 2
with the other body sites. These studies highlight the variation in
70 2
SC ceramides that influence lamellar organization, including the
long-periodicity phase (LPP) and intermolecular orthorhombic
packing. Clearly, careful consideration needs to be given to body
site in the design of any study in which changes in ceramide
have confirmed the presence of orthorhombic and hexagonally composition will be measured.
packed lipids in isolated human SC and in a range of ceramide con-
taining SC lipid models. Biophysical studies of complex mixtures of
Seasonal variation
SC lipids, isolated SC and even in vivo SC lipids are a vast and
growing topic well beyond the ceramide focus of this review. Declining levels of ceramides and especially CER [EOS]-linoleate
The careful interpretation of many in vitro and in vivo investiga- have been reported from summer to winter [29]. However, these
tions on lipid behaviour in the SC has led to several models being studies are in marked contrast to that reported by Yoshikawa et al.
proposed to describe lipid organization in this structure. Some mod- [32] for Japanese subjects. Furthermore, Ishikawa et al., also
els are more theoretical/hypothetical, such as Norlen’s ‘single gel observed seasonal variation in ceramide levels on several body sites
phase’ model [27], whereas others are based on selected empirical (arm, hand and lip) and decreases in CER [EOS] and [EOH] on
data, such as Bouwstra’s sandwich model that relies primarily on cheek and hand body sites. Similarly, ceramide chain lengths were
X-ray diffraction data [23]. Over the last decade no significant new slightly shorter in winter [31]. These findings need to be taken into
models have been proposed for SC lipid organization while the pres- consideration if any skin barrier study is conducted across the
ence of orthorhombic lipid organization in both ex vivo and in vivo seasons.

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Stratum corneum ceramides
Ageing
Rogers et al. [29] reported declining levels of SC ceramides and
CER [EOS]-linoleate with age. Clearly, these changes can influence
the packing states of SC lipids. Indeed Tfyali et al. [33] observed a
lower content of ordered alkyl chains in SC lipids of older volun-
teers. Given, the well recognized changes in the gross properties of
aged skin, it is not surprising that barrier lipid composition and
organization are different.
Ethnicity
African American subjects have been reported to have the lowest
levels of forearm SC phytosphingosine-containing ceramides [34],
whereas ceramide levels in East Asian subjects were reported to be
identical to Caucasians. However, Jungersted et al., [35] found
increased forearm ceramide/cholesterol ratios for Asian subjects
compared with Africans and Caucasians with Africans having the
lowest values; however, there were no differences in the relative
composition of ceramides. Cleary much more work is needed in this
area.
Xerosis, dandruff and acne
Fulmer and Kramer originally reported on increased CER [NS], CER
[EOP] and CER [EOH] and decreased CER [NP] in surfactant-
induced dry leg skin together with increased short-chain fatty acids
the importance of which was nor realized at that time [36]. In
hand skin suffering from soap-induced winter xerosis, Rawlings
et al. found the total levels of SC ceramides are decreased, and the
levels of fatty acids are increased [37] leading to aberrations in the
SC lamellar organization revealed by electron microscopy. In con-
trast, Akimoto et al. [38] however, reported increased ceramides in
xerotic leg skin with no differences in their relative composition.
However, Schreiner et al. [39] reported that there is a large
intra-individual difference in lipid levels without obvious physical
manifestations of dryness. Similarly, in aged dry leg skin the demon-
stration of an altered lipid composition or differing molecular organi-
zation is not always apparent. Ishikawa et al., [31] demonstrated
that all ceramide species decreased with skin dryness, roughness and
scaliness on legs, and this was significant for CER [EOP], [NDS],
[NH], [NP], [ADS], [AH] and [AP], but there was no change in cera-
mide chain lengths. Tamura et al. [40] also reported that lip rough-
ness correlated with decreased CER [NH], [NP], [AH], [EOS] and
[EOH]. Dandruff is also a scaling disorder associated with decreased
levels of CER [EOS] and [NP] [41]. Reduced proportions of ceramides
and especially linoleate-containing CER[EOS] have been reported in
acne patients, and it has been postulated that this reflected a localized
decrease in the bioavailability of the essential fatty acid due to a dilu-
tion effect of increased sebum production [16].
Clearly reduced overall levels of ceramides and decreases in
specific ceramides classes contributes to the incidence of xerosis,
although the specific impact on lipid phase behaviour changes still
wait to be identified. Changes in the composition and levels of
facial ceramides await further study. Nevertheless, deficiencies of
CER[EOS] and CER[EOH] are frequently correlated with an absence
of the LPP in dry skin and associated with abnormalities in SC
lamellar architecture [39]. The routine availability of new sensitive
analytical methods necessitate that many studies should be
repeated to confirm the reported changes in ceramides and other
lipid classes.
370 © 2017 Society of Cosmetic Scientists and the Soci
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D. J. Moore and A. V. Rawlings
Ichthyoses, psoriasis, Netherton syndrome and atopic dermatitis
Recent reports of lipid abnormalities in subjects with Ichthyoses,
psoriasis, Netherton syndrome and atopic dermatitis have been
reviewed by Elias et al. [42] and van Smeden et al. [43], and the
main references can be found in their reviews. Individuals suffering
from lamellar ichthyosis have a defective gene for transglutaminase
1 leading to fragile corneocytes with reduced quantities of CBL.
Decreased free fatty acid/cholesterol and free fatty acid/ceramide
ratios have been reported as well as a reduction in CER [EOS] and
[NP] in these patients [43]. Corresponding changes in lamellar
architecture were observed as well as increased hexagonal lipid
packing. Equally, the genetic basis of the congenital scaling syn-
drome harlequin ichthyosis has pointed to the importance of muta-
tions in the ABCA12 transporter, which leads to an abnormality in
lamellar body formation, decreases in CER[EOS], perturbed lamellar
lipid organization in the SC and loss of barrier function [43]. More-
over, mutations in ceramide synthase 3 have also been shown to
be a cause of autosomal recessive congenital ichthyosis that leads
to a specific loss of ceramides with very long acyl chains from C26-
C34 [44]. In Refsum disease, the SC intercorneocyte space has also
been reported to be non-uniform with some areas having appropri-
ate lamellar structures and others that completely lacked them
[45]. In many cases, a complete absence of corneocyte lipid envel-
opes was also observed. Sjogren–Larsson syndrome is caused by
mutations in the fatty aldehyde dehydrogenase gene (ALDH3A2),
and SC fatty acids and CBL were reported to be increased two-fold,
while levels of CER[EOS], CER[AP] and CER[AH] were decreased
[46]. Deficiencies in the levels of acylceramides including CER
[EOS] and CBL (decreased CER A/B derived from CER [EOS] and
[EOH], respectively) have also been reported in the neutral lipid
storage disorder Dorfman–Chanarin syndrome [47]. The lack of
covalently bound lipids can easily be seen under the electron
microscope. In X-linked ichthyosis, cholesterol sulphate levels are
significantly increased and may exceed 10% of total lipid mass
leading to changes in barrier lipid phase behaviour [42].
Although considered as an ichthyoses associated with protease–
anti-protease imbalance abnormalities in SC lipids also occur in
Netherton syndrome. The total amounts of SC ceramides are
reduced, while the levels of shorter chain ceramides (C32-38) and
unsaturated ceramides are increased [43]. Of all the ceramide sub-
classes, CER[NP] and the acylceramides were the most significantly
reduced, whereas CER[AS], CER[NS] and CER[AH] were the least
affected. Glucosylceramides are also increased indicating a lack of
their processing. Reduced LPP and increased hexagonal packing
were apparent.
Decreases in the levels of CER [EOS], [NP], [AP] and increases in
CER [NS] and [AS] are reported in subjects with psoriasis [43].
Increased cholesterol and decreased fatty acid fraction are also
reported. A shortening of ceramide chain length being dictated by
the chain length of the amidated fatty acid has been observed in
subjects with psoriasis. The proportion of CER[NH] with total
higher carbon number between 40 and 43 was higher, whereas
C47-50 was lower compared to healthy controls. Similar changes
were observed for CER[AdS], CER[NP] and CER[AP]. Equally, the
composition of the CBL also differs in psoriatic SC with decreases in
the levels of CER[OH] and increases in x-hydroxy acids and fatty
acids, particularly oleate and linoleate. Reduced presence of the
LPP is known.
Decreased levels of SC ceramides in non-inflamed plantar skin
of subjects with atopic dermatitis (AD) are well known. Decreased
International Journal of Cosmetic Science, 39, 366–372
Stratum corneum ceramides D. J. Moore and A. V. Rawlings

levels of forearm SC CER[EOS] accompanied by increased levels of
esterified oleic acid in the remaining CER[EOS] have been
reported [43]. In addition, a reduced ceramide/cholesterol ratio
has been observed in lesional skin. More recently, increased levels
of Cer[AS] in AD patients have been observed, while larger cera-
mide species (>50 carbons) were expressed at lower levels in CER
[NS], CER[NdS], CER[NH], CER[AS] and CER[AH], while smaller
species (<40 carbons) were observed at higher levels in CER[NS],
CER[NdS] and CER[AS]. CER[EOS], CER[EOP] and CER[EOH] were
all observed at lower levels. Decreased levels of the EO species of
ceramides including CER[EOdS] and increased levels of CER[NP]
were also reported. Furthermore, elevated levels of C34 fatty acid
chain length species were observed in ceramide subclasses CER
[AS], CER[AH], CER[NS] and CER[NH]. Overall, the average cera-
mide chain length significantly decreased by 0.64  0.23 total
carbon atoms in AD [43]. An increased level of ceramide syn-
thase-4 contributes to the increased synthesis of the shorter chain
ceramides [48]. When focusing on lateral lipid organization AD
patients show a less dense lipid packing compared with control
patients that correlates strongly with a higher level of C34
ceramides. This finding demonstrates that ceramide chain length
is an important determinant of the lateral lipid organization in
SC [43].
All of these studies further demonstrate that abnormalities in
ceramide composition, physical properties and lamellar architecture
contribute to barrier failure. Further developments in analysis
methodologies will contribute to the understanding of SC ceramide
composition in such conditions [49, 50].
Conclusions
Our understanding of the structure, function and pathophysiology of
SC lipids has evolved over the last two decades. Moreover, as our
techniques of investigation have become increasingly more sophisti-
cated, it has become very evident that our understanding of these
molecules remains in its infancy. As an example the observations
that the SC contain over 300 and possibly up to 1000 distinct cera-
mide species, derived from 13 classes, suggests an exquisitely subtle
relationship between the types of ceramides and physical and chemi-
cal behaviour. Nevertheless, an increasing body of research has
demonstrated the importance of the correct SC lipid lamellar archi-
tecture with conformationally ordered lipid bilayers, the presence of
long-chain ceramides (as either free or covalently bound lipids),
increased levels of phytosphingosine-containing ceramides and a
high SC lipid/protein ratio for optimal barrier function. Clearly, there
is much more to be learned but as we further decipher the complexity
of SC lipids and understand their individual roles in the SC, we will
learn how to better treat disorders of cornification.
Acknowledgment
DJM is an employee of GSK. AVR is a consultant to GSK.

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