Chemistry and Physics of Lipids 236 (2021) 105055

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Chemistry and Physics of Lipids

journal homepage: www.elsevier.com/locate/chemphyslip

Skin lipids in health and disease: A review

Sophie Knox, Niamh M. O’Boyle *
School of Pharmacy and Pharmaceutical Sciences, Panoz Institute, Trinity College Dublin, D02 PN40, Ireland

A R T I C L E I N F O A B S T R A C T

Keywords: Our skin is the interface between us and our environment – a flexible barrier that has evolved for protection,
Skin lipids immunity, regulation and sensation. Once regarded as inert, we now know that it is a dynamic environment. Skin
Atopic dermatitis lipids are crucial to the structure and function of skin. From deep in the hypodermis, through the ceramide-rich
Psoriasis
epidermis, to the lipids of the skin surface, there are a vast array of different lipids with important roles to play.
Ceramide
Fatty acids
This review firstly discusses the lipid composition of human skin and secondly, changes that have been found in
Triacylglycerol skin lipid composition in different skin diseases. Further research into skin lipids facilitated by ever-improving
Diacylglycerol methodologies will no doubt generate new knowledge, paving the way for diagnosis, prevention and treat­
Acne ment of skin disorders and diseases.
Allergic contact dermatitis

1. Introduction 2. Lipids in the epidermis

The skin is a large, complex organ with a multitude of functions,
including barrier, immunity and sensation. It is structured in distinct
layers: the epidermis (outermost layer), dermis (middle layer) and hy­
podermis (innermost layer) (Fig. 1A). Lipids are one of the fundamental
components of the skin. There is a vast array of hydrophobic molecules
which play a key role in the skin’s barrier function, inhibiting excessive
transcutaneous evaporative water loss (TEWL) and preventing entry of
microbes, allergens and other xenobiotics. The lipophilicity of skin
prevents diffusion of hydrophilic molecules. Several lipid subclasses
possess antibacterial activity including sphingoid bases on the skin
surface (Becam et al., 2017). The fascinating topic of antimicrobial lipids
has been reviewed comprehensively elsewhere (Fischer, 2020; Drake
et al., 2008; Wertz, 2018). Over the years, numerous studies have shown
an association between the skin’s lipid composition and diseased skin,
including psoriasis and atopic dermatitis (Sahle et al., 2015). In this
review, we will firstly discuss the lipid composition of human dermis
and epidermis and secondly, variations in lipid composition between
healthy and diseased states in human skin.
The outermost skin layer, the epidermis, is a lipid-rich region that
provides structural support and limits entry of chemicals. The extra­
cellular space of the epidermis is dominated by lipids, mostly ceramides,
acylceramides, cholesterol, cholesterol esters, and non-esterified fatty
acids (NEFA, commonly referred to as free fatty acids) arranged in
multiple bilayers. The epidermis is classified into four sublayers: the
stratum corneum (SC, outermost), stratum granulosum (SG), stratum
spinosum (SS) and stratum basale (SB, innermost) (Fig. 1B). The three
innermost epidermal sublayers are often referred to collectively as the
viable epidermis. As studies are performed either on whole (full-thick­
ness) epidermis or viable epidermis, we indicate the specific layer
investigated throughout the article by referring to full-thickness
epidermis (includes the SC) or viable epidermis (without the SC).
2.1. Lipids in the stratum corneum
The outermost epidermal layer, the stratum corneum (SC), measures
10− 20 μm thick (Mohammed et al., 2012). It is actively involved in the
innate immune system, forming a physical barrier between the external
environment and the body. The SC is the most extensively studied skin

Abbreviations: AD, atopic dermatitis; ACD, allergic contact dermatitis; CER, ceramide; DAG, diacylglycerol; FFA, free fatty acid; HPLC, high performance liquid
chromatography; HS, hidradenitis suppurativa; MUFA, monounsaturated fatty acid; NEFA, non-esterified fatty acid; PPR, papulopustular rosacea; PUFA, poly­
unsaturated fatty acid; SB, stratum basale; SC, stratum corneum; SG, stratum granulosum; SS, stratum spinosum; TAG, triacylglycerol; TEWL, transepidermal water
loss.
* Corresponding author.
E-mail address: nioboyle@tcd.ie (N.M. O’Boyle).

https://doi.org/10.1016/j.chemphyslip.2021.105055
Received 13 November 2020; Received in revised form 20 January 2021; Accepted 21 January 2021
Available online 6 February 2021
0009-3084/© 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
S. Knox and N.M. O’Boyle
Fig. 1. A. Skin structure showing epidermis, dermis and hypodermis. B.
Epidermal structure showing the four sublayers – stratum corneum (SC), stra­
tum granulosum (SG), stratum spinosum (SS) and stratum basale (SB). Adjacent
keratinocytes are connected via desmosomes. Keratinohyaline granules contain
profilaggrin which aggregates keratin proteins in the SC. Lamellar bodies
contain lipids which are expelled into the border between the SG and SC.
layer. Tape stripping is a valuable technique for obtaining SC samples
(Kim et al., 2019; Lademann et al., 2009; Koppes et al., 2016). When
combined with other analytical techniques such as spectrometry or
chromatography, tape stripping is a powerful tool for analysing and
quantifying lipids in the SC (Ezerskaia et al., 2018; Weerheim and
Ponec, 2001). This combined approach can be used to observe the cor­
relation between lipids in healthy skin and skin diseases with a
compromised epidermal barrier. A major hurdle in the analysis of skin
lipids is the structural similarity between many SC lipids, with similar
fragmentation ions in mass spectrometry or similar retention times in
chromatography. Open access software including LipidMaps and Lip­
idCreator are invaluable tools to aid the identification of specific lipids.
The SC is a complex matrix with a relative composition of protein
(75–80 %) and lipids (5–15 %) (Sahle et al., 2015). The architecture of
the SC can be represented as a ‘brick-and-mortar’ arrangement, with
dense, anucleate protein-rich keratinocytes (corneocytes) symbolising
the bricks that are embedded in lipid mortar (van Smeden and Bouwstra,
2016). The SC consists of 15–25 layers of corneocytes. The cross-linked
surface proteins of corneocytes, known as the cornified envelope, are
covalently bound to intercellular ω-hydroxyceramides that form the
corneocyte lipid envelope, surrounding the cell (Elias et al., 2014).
These cells originate in the SB and differentiate progressively on their
journey through the different epidermal layers (SB, SS and SG, Fig. 1B).
When the corneocytes migrate from the innermost epidermis to the SC,
there is a notable change in the lipid composition. Phospholipids are
enzymatically degraded to form glycerol, free fatty acid chains and
2
Chemistry and Physics of Lipids 236 (2021) 105055
glucosylceramides which can be used to form ceramide molecules. The
continual depletion and negligible levels of phospholipids in the SC is
unique, as typical keratinocyte plasma membranes have high levels of
phospholipids (Lampe et al., 1983). The lipids are supplied by lamellar
granules (also known as lamellar bodies) which are found in high con­
centrations in the upper viable epidermis, the SG. Lamellar granules are
secretory organelles containing many lipid subtypes and enzymes (e.g.
glucosylceramides, sphingomyelin and phospholipids) which are
released via exocytosis at the SC/SG interface (Feingold, 2012).
Co-secretion of enzymes process the precursor lipids into hydrophobic
barrier constituents (Schmitz and Müller, 1991).
Lipids are the ‘mortar’ of the SC holding the corneocyte ‘bricks’ in
place. When compared to other factors such as thickness of the SC, the
quantitative changes in lipid content appear to be most important in
predicting skin permeability (Rawlings et al., 1994). There is an intricate
multilamellar lipid membrane in the SC, described by several models,
including the domain mosaic model (Forslind, 1994), the sandwich
model (Bouwstra et al., 2000) and Kieslev’s model (Kiselev et al., 2005).
In silico molecular dynamics simulations are a recent useful technique
(Das and Olmsted, 2016). These are beyond the scope of this review and
have been discussed comprehensively elsewhere (Boncheva, 2014;
Schroeter et al., 2015). It is clear that interdisciplinary research is
needed to fully characterise the complexities of SC lipid organisation.
Intercellular lipids comprise of 15 % of the SC weight (Coderch et al.,
2003). The relative composition of skin lipids in the SC is very different
to the viable epidermis and dermis. The SC is composed of three major
lipid subclasses: ceramides, cholesterol, and NEFA (Fig. 2) (Boncheva,
2014). It contains negligible amounts of phospholipids, as mentioned
above. Each of these is considered separately below. It is notable that the
lipid composition of the SC varies by anatomical site, with different
extents of variation for different lipid subclasses (Lampe et al., 1983;
Starr et al., 2016). Lipids also vary by age, sebaceous gland density
(Ludovici et al., 2018) and UV exposure, e.g. levels of cholesterol sulfate
and the fatty acids lignoceric acid (C24:0) and hexacosanoic acid
(C26:0) (Starr et al., 2016). Physiological variation in lipid content is
important to consider during analysis. Population factors can also play a
confounding role in SC lipid compositions such as age (Starr et al., 2016;
Choe et al., 2018), gender (Rogers et al., 1996), and seasonal variation
(Rogers et al., 1996; Wang et al., 2020). The diversity of influential
factors contributes to intra-patient and inter-patient variability in skin
lipid composition and vastly increases the complexity of lipidomic
analysis.
2.1.1. Ceramides in the stratum corneum
Ceramides (CERs) consist of a hydrophobic fatty acid chain linked to
an amino-containing sphingoid base. The linkage is achieved via an
Fig. 2. Lipid composition of healthy stratum corneum by dry weight as a
percentage of total lipid content. Percentage contribution of ceramides (50 %),
non-esterified fatty acids (NEFAs)(10 - 15 %), cholesterol (27 %), cholesterol
esters (10 %), and cholesterol sulfate (2-5 %) is shown (Boncheva, 2014;
Coderch et al., 2003; Feingold, 2007).
S. Knox and N.M. O’Boyle
amide bond between the carbonyl group of the carboxylic acid of the
fatty acid chain and the amino group of the base. In human SC, many
ceramide subclasses have been identified in varying quantities (Table 1).
The different ceramide subclasses are continually expanding with more
species being identified in the last decade. CERs were originally classi­
fied into nine subclasses, [NS], [AS], [EOS], [NP], [AP], [EOP], [NH],
[AH] and [EOH] (Masukawa et al., 2008). These CERs contained one of
sphingosine [S], phytosphingosine [P] or 6-hydroxysphingosine [H] as
the sphingoid base linked to one of non-hydroxy fatty acid [N],
alpha-hydroxy fatty acid [A], or esterified omega-hydroxy fatty acid
[EO] as the fatty acid chain. By 2010, further investigation using liquid
chromatography coupled with mass spectroscopy led to the discovery of
the dihydrosphingosine base [DS], extending the CER to 16 potential
subclasses (Table 1) (Masukawa et al., 2008; Farwanah et al., 2005a).
EOdS lipids were identified in human SC in 2011 (van Smeden et al.,
2011). Recently, the number of subclasses in human SC was extended to
21, including identification of the 4,14-sphingadiene [SD] base in
human skin for the first time (Kawana et al., 2020). It is entirely possible
that other bases will be discovered as new analytical techniques and
more sensitive methods become available. For example, 1-O-acyl
omega-linoleoyloxy ceramides [1-O-E (EO) Cer] recently identified in
the EpiSkin human reconstructed epidermis model are not yet known in
human skin (Assi et al., 2020).
The most abundant subclasses in human SC, in samples taken from
the inner forearm, are [NP] and [NH], with relative compositions of
22.1–24.2 % and 14.5–23.7 % respectively. Fatty acid chain lengths of
C24 and C26 are the most common (Kawana et al., 2020; Sjövall et al.,
2018; t’Kindt et al., 2012). Ceramides with odd-numbered fatty acid
chain lengths are also identified in skin, potentially related to the
metabolism of phytosphingosine (Hinder et al., 2011; Kondo et al.,
2014). Approximately 12 % of [NP] and [EOS] in human SC are
odd-numbered (Hinder et al., 2011). The existence of a ceramide
gradient across the SC has been investigated but there is currently
conflicting evidence to support its existence (Jungersted et al., 2008).
The CERs fatty acid chains found in the SC are primarily long,
saturated hydrocarbon chains (Boncheva, 2014). As noted above, the
most commonly found fatty acid hydrocarbon chains are between
C24− 26 whereas the prevalent amide base hydrocarbon chains are
Table 1
Ceramides identified in human SC. There are five well-known amino bases (S, P, H, DS and SD) and four fatty acid chains (N, A, O and EO). A further amino base (T) has
also been described (t’Kindt et al., 2012). Different alkyl chain lengths and degrees of unsaturation in both the amino base and fatty acid chains are possible giving rise
to a huge number of individual ceramides.
FATTY ACID CHAIN
Sphingosine [S]
Phytosphingosine [P]
6-Hydroxysphingosine [H]
AMINO
BASE
Dihydrosphingosine [DS]
4,14-Sphingadiene [SD]
Dihydroxy-dihydrosphingosine or
Dihydroxysphinganine [T] (t’Kindt et al., 2012)
Chemistry and Physics of Lipids 236 (2021) 105055
between C18− 22. The length of the fatty acid chain influences skin
permeability (Skolová et al., 2013). Short-chain ceramides do not
maintain the barrier properties of the long-chain ceramides, despite
having the same polar headgroups and hydrogen bonding ability. The
highest permeability was found in the ceramides containing between
four and six carbon fatty acid chains. The short aliphatic chain may not
be long enough for effective interactions with other lipid chains, para­
mount in the lamellar architecture of the SC. Lipid membrane models
indicate that the sphingoid base of omega-O-acylceramides, with
ultra-long carbon chains ≈32, significantly affects membrane architec­
ture and permeability (Opálka et al., 2020).
The many ceramide subclasses and the unique arrangement of po­
tential fatty acid hydrocarbon chains has led to a multitude of hetero­
geneity between the ceramide molecules found in the SC (>400
ceramide species have been identified); hence, CER composition is
extremely difficult to predict.
2.1.2. Cholesterol in the stratum corneum
Cholesterol and its derivatives are lipophilic steroids with a rigid,
four ring (ABCD) structure. Cholesterol has a free alcoholic group on
ring A (highlighted in red, Fig. 3). It comprises approximately 27 % of
the lipid content of the SC and is important for the fluidity and rigidity of
the SC (Fig. 2). The sterol contributes to the correct lamellar and lateral
structure. Cholesterol esters contribute 10 % to the SC lipid content.
Cholesterol sulfate is a sulfated derivate of cholesterol (Fig. 3). It is a
minor component, comprising of 2–5 % of the total lipids in the SC
(Fig. 2). Cholesterol sulfate is generated in the viable epidermis by
cholesterol sulfotransferase. However, it is also desulfated in the viable
epidermis by steroid sulfatase creating a ‘cholesterol sulfate cycle’. The
function of the sulfate ester is not fully understood; however, it is
believed to be involved in the SC cohesion and regulation of desqua­
mation. A study conducted by Long et al. found that the level of
cholesterol sulfate was significantly decreased in desquamated material
(Long et al., 1985). The ratio of cholesterol:cholesterol sulfate is
significantly altered in recessive X-linked ichythosis (Elias et al., 2008),
as described in Section 3.5.
Non-hydroxy fatty α-Hydroxy fatty ω-Hydroxyl fatty Esterified ω-hydroxyl fatty
acid [N] acid [A] acid [O] acid [EO]
[NS] [AS] [OS] [EOS]
[NP] [AP] [OP] [EOP]
[NH] [AH] [OH] [EOH]
[NDS] [ADS] [ODS] [EODS]
[NSD] [ASD] [OSD] [EOSD]
[NT]
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S. Knox and N.M. O’Boyle Chemistry and Physics of Lipids 236 (2021) 105055

Table 2
Structures of non-esterified fatty acids (NEFAs, also known as free fatty acids) found in human skin. Relative composition is shown in Fig. 4.
Saturated and unbranched fatty acids

Dodecanoic acid (C12:0)

Myristic acid (C14:0)

Palmitic acid (C16:0)

Stearic acid (C18:0)

Eicosanoic (arachidic) acid (C20:0)

Behenic acid (C22:0)

Lignoceric acid (C24:0)

Hexascosanoic acid (C26:0)

Monounsaturated fatty acids (MUFA)

Myristoleic acid (C14:1, n-5)

Palmitoleic acid (C16:1, n-7)

Sapienic acid (C16:1, n-10)

Oleic acid (C18:1, n-9)

Polyunsaturated fatty acids (PUFA)

Linoleic acid (C18:2, n-6)

Arachidonic acid (C20:4, n-6)

Eicosapentaenoic acid (C20:5, n-3)

Docosahexaenoic acid (C22:6, n-3)

2.1.3. Fatty acids in the stratum corneum

Fig. 3. Chemical structures of the lipophilic steroid cholesterol and derivatives
found in skin.
The majority of barrier non-esterified fatty acids (NEFAs) and fatty
acids bound to ceramides in the SC are saturated and unbranched, hy­
drocarbon chains of length between C16− 26 (Nicollier et al., 1986).
Research into full-thickness human epidermial NEFA (including SC)
composition by Chapkin (Chapkin et al., 1986) indicate the presence of a
diversity of NEFA (Fig. 4) (Niki, 2015). The main NEFAs in this study
include palmitic acid (C16:0), stearic acid (C18:0), behenic acid (C22:0),
lignoceric acid (C24:0) and hexacosanoic (cerotic) acid (C26:0) (Fig. 4A
and structures in Table 2) (Ananthapadmanabhan et al., 2013; van
Smeden et al., 2014a). The terminal carboxylic acid functional group
(COOH) contributes to the acidity of the skin. Lignoceric acid (C24:0)
and hexacosanoic acid (C26:0) make up 50 % of the net weight of the
NEFA content in SC samples obtained by tape stripping from human ex
vivo skin (ventral forearm). The shorter chain fatty acids such as palmitic
acid (C16:0) and stearic acid (C18:0) are located closer to the external
surface. Monounsaturated NEFA such as oleic acid (C18:1, n-9) and
polyunsaturated NEFA such as eicosapentaenoic acid (C20:5, n-3), do­
cosahexaenoic acid (C22:6, n-3) and linoleic acid (C18:2, n-6) are pre­
sent in smaller quantities (25 % of total NEFA). Several longer chain
fatty acids from C21:0 to C28:0 are also present (Sjövall et al., 2018). Of
note, odd-numbered NEFAs comprised about 21 and 23 % of total NEFAs

4
S. Knox and N.M. O’Boyle Chemistry and Physics of Lipids 236 (2021) 105055

Fig. 4. Average percentages of A. fatty acids in full-thickness human epidermis and B. fatty acids in human sebaceous lipids. Adapted from Chapkin (n = 12)
(Chapkin et al., 1986) and Ní Raghallaigh (n = 24) (Ní Raghallaigh et al., 2012). Note that significant differences in sebaceous fatty acid content were observed
between males and females, not shown here. ‘Other’ includes sixteen fatty acids with concentrations less than 1 % each of total (Ní Raghallaigh et al., 2012).

in the stratum corneum of subgroups elderly/healthy and young/­
healthy, respectively (Wohlrab et al., 2018). This includes C21:0, C23:0,
C25:0 and C27:0 (Sjövall et al., 2018). The composition of fatty acids in
the SC, as with other lipids, varies by anatomical site with a higher
percentage in the face and abdomen compared to leg and plantar human
SC (Lampe et al., 1983).
The concentration of NEFA varies throughout the regions of the skin.
The amount of epidermal NEFA is decreased in areas with higher den­
sities of sebaceous glands (Ludovici et al., 2018). Sebaceous gland lipids
are discussed further in Section 2.3.
The concentration of unsaturated, shorter FFA increases in patho­
logical conditions such as atopic dermatitis (Vávrová et al., 2017). This
is comparable to the ceramide lipids. As the hydrocarbon chain de­
creases in length, the lamellar structure is compromised, altering the
permeability of the skin.
2.1.4. Triacylglycerols and diacylglycerols
Triacylglycerols (TAGs) are triesters of fatty acids formed from
glycerol and three fatty acids (Fig. 5). They are known as simple TAGs if
the three fatty acid chains are the same, or mixed TAGs if the three fatty
acid chains differ. They are a minor component of the lipid matrix in the
SC (Radner and Fischer, 2014). Nonetheless, the metabolism of TAGs is
influential in epidermal differentiation and the skin’s barrier function.
Hydrolysis of TAGs forms fatty acids required for the synthesis of
omega-O-acylceramides, found in the cornified lipid envelope. TAGs
and diacylglycerols (DAGs) found in the SC are delivered by sebum on
the skin’s surface. Lipidomic studies suggest that these glycerides
penetrate roughly 5–7 layers within the SC before the levels begin to
plateau (Sadowski et al., 2017). DAGs, assumed to represent TAGs due
to fragmentation in the MS method used, were found at the skin surface
in another study (Sjövall et al., 2018).
2.2. Lipids in the viable epidermis and dermis
Sampling skin lipids beyond the SC normally requires examination of
viable cells (Kendall et al., 2018). Due to the difficulty associated with
obtaining samples for full-thickness skin biopsy and the need for speci­
alised analytical equipment, less research has been conducted on the
composition of lipids in full-thickness epidermis and dermis compared
to SC. Different mass spectrometry instrumentation has been extremely
useful for studies of whole skin, e.g. the works of Sjövall and Kendall
(Sjövall et al., 2018; Kendall et al., 2017). Confocal Raman spectroscopy

5
S. Knox and N.M. O’Boyle
Fig. 5. General structure of triacylglycerols (TAGs), diacylglycerols (DAGs) and monacylglycerols (MAGs). Ester linkage is highlighted in red.
is an evolving technique of interest that will be useful for in vivo studies
(Darlenski and Fluhr, 2016; Förster et al., 2011; Tfayli et al., 2014). The
emerging use of powerful chromatography and spectroscopy analytical
techniques to examine the lipid composition in the whole skin has
proven to be extremely insightful for lipidomic analysis. These studies
have also been useful for determining changes that occur in lipid
composition in diseased skin.
The viable epidermis, measuring 50− 100 μm, consists of the three
remaining epidermal layers: the SG, SS and the innermost SB (Fig. 1B)
(van Smeden et al., 2014b). SB contains proliferating keratinocytes
which migrate towards the SC, until released from the skin’s surface
(desquamation). During the journey to the skin surface, the keratino­
cytes differentiate to form the characteristic flattened dead cells (cor­
neocytes) found in the SC. The SB is made up mostly of phospholipids
(70 %), cholesterol and derivatives (13 %), and TAGs (11 %). Terminal
differentiation of keratinocytes drastically changes the lipid composi­
tion and, in the SG (the last stratum that contains nucleated keratino­
cytes), intracellular organelles termed lamellar bodies are formed in
which glucosylceramides, phospholipids and sphingomyelin are stored
(Jiang and Feingold, 2011).
2.2.1. Cholesterol, cholesterol sulfate, triacylglycerols (TAGs) and
ceramides in epidermis and dermis
Amongst the lipids already discussed above in Section 2.1, choles­
terol, cholesterol sulfate, cholesterol esters, ceramides, TAGs and fatty
acids are also present in the viable epidermis. Cholesterol was detected
relatively consistently throughout a whole skin cross section including
the viable epidermis (Sjövall et al., 2018). In general, the ratio of
cholesterol: cholesterol sulfate is much lower in skin (as low as 5:1)
compared to elsewhere in the body (500:1). Cholesterol sulfate appears
in the viable epidermis up to a depth of 200 μM from the skin surface,
mainly in the region just below the SC (Sjövall et al., 2018). This is
consistent with previous observations that the upper SG is rich in
cholesterol sulfate, where it comprises 4–5 % of total lipid content
(Strott and Higashi, 2003). TAGs (indicated largely by DAG ions and low
yields of intact TAG ions on the ToF-SIMS instrument) are found in high
concentrations in the areas deep in the dermis, SC and SB.
Ceramides are the predominant lipid in the epidermis, comprising 50
% of the overall lipid content. Kendall et al. compared the presence of
ceramides in full-thickness epidermis and dermis from four female
donor skin samples using LC–MS (Kendall et al., 2017). Eight ceramide
subclasses were located in the dermis and eleven subclasses were present
in full-thickness epidermis, in varying amounts. Esterified ω-hydroxyl
6
Chemistry and Physics of Lipids 236 (2021) 105055
fatty acid-containing ceramides [EO] were not identified in the dermis.
The dominant ceramide found in the dermis was the sphingosine amide
base linked to a non-hydroxy fatty acid chain [NS], making up 53.4 % of
the total ceramide found in the dermis and 34.5 % of total ceramide in
full-thickness epidermis (Fig. 6). This is in contrast to the SC, where [NP]
and [NH] ceramides were found in the highest concentrations (Section
2.1.1).
The ceramide subclasses interact (both intermolecularly and intra­
molecularly) with other lipids forming the characteristic densely packed
three-dimensional structures known as the lipid lamellae (Coderch et al.,
2003). The highly ordered architecture is important for the structural
integrity and barrier function of the skin. Ceramides are the principal
component of the lamellar bodies and the multilamellar barrier. Intra­
cellular ceramides act as second messengers for numerous signalling
pathways including apoptosis, cell growth and differentiation. The
metabolism of ceramides may suppress the apoptotic process. Therefore,
ceramides have both important intracellular and intercellular roles in
the skin’s barrier function (Cha et al., 2016).
2.2.2. Phospholipids in viable epidermis and dermis
Phospholipids are not present in the SC but are distributed
throughout the viable epidermis and dermis. Phospholipids are amphi­
philic molecules, with polar head groups derived from phosphoric acid,
together with long hydrocarbon chains which impart hydrophobicity to
the molecule. They are the main subclass of lipids in viable keratino­
cytes. Phospholipids are further subclassified into two main groups:
phosphoglycerides derived from glycerol or sphingolipids which have a
dihydroxyamine (sphingosine) backbone. Phosphoglycerides (glycer­
ophospholipids) have a general structure consisting of two fatty acids
linked via ester bonds to two of the hydroxyl groups of glycerol, whilst
the third hydroxy group is esterified with a phosphate side chain (Fig. 7);
this however is variable and phosphoglycerides with, for example, two
or more phosphate side chains have also been characterised.
Phospholipids are relatively homogenously distributed across the
viable epidermis (Sjövall et al., 2018). Twelve phospholipid subtypes
have been detected in whole skin tissue including the phosphoglycerides
phosphatidic acid (PA), phosphatidyl ethanolamine (PE), cardiolipin
(CL), phosphatidylserine (PS), lysophosphatidylcholine (LPC), phos­
phatidylinositol (PI), alkylacylglycerophosphocholine (AAPC), etha­
nolamine plasmalogen (Eplas) and phospatidylcholine (PC) and the
sphingolipids dihydrosphingomyelin (DHSM) and sphingomyelin (SM)
(Fig. 8) (Sjövall et al., 2018; Meneses et al., 1998). PC was by far the
most abundant phosphoglyceride in both epidermis and dermis,
S. Knox and N.M. O’Boyle
Fig. 6. Ceramides detected in the dermis (blue) and full-thickness epidermis (orange) of ex vivo human abdominal skin (n = 4, all donors were female) (Kendall
et al., 2017).
Fig. 7. General structures of phospholipid subclasses: phosphoglycerides and sphingomyelins.
followed by the sphingolipid SM. PE intensity was observed to increase
in deeper layers of the epidermis, consistent with their presence in viable
cell membranes (Sjövall et al., 2018).
Variation in the levels of phospholipids have also been detected in
diseased skin conditions, e.g. psoriasis, further discussed in Section 3.2.
2.2.3. Vitamins D and E
Vitamin D is a lipophilic secosteroid hormone which is synthesised
within the skin during exposure to UV radiation from sunlight. Vitamin
D has a variety of functions within the skin including keratinocyte
proliferation, differentiation, and apoptosis. These processes are essen­
tial for maintaining the integrity of the skin’s architecture and therefore,
its protective barrier role. Keratinocytes in the epidermis can synthesise
7
Chemistry and Physics of Lipids 236 (2021) 105055
Fig. 8. Phospholipid subclasses detected in human epidermis
(blue) and dermis (orange) by 31P nuclear magnetic resonance
and expressed as mole percentages (n = 7). Phospatidylcholine
(PC); phosphatidic acid (PA), ethanolamine plasmalogen
(Eplas); phosphatidyl ethanolamine (PE); phosphatidylserine
(PS); lysophosphatidylcholine (LPC); phosphatidylinositol (PI);
alkylacylglycerophosphocholine (AAPC); cardiolipin (CL);
sphingomyelin (SM); dihydrosphingomyelin (DHSM); UK =
unknown (Meneses et al., 1998).
vitamin D, which is the primary source of vitamin D in the body. Pre­
vitamin D is formed when 7-dehydrocholesterol (7-DHC, provitamin D)
is exposed to ultraviolet radiation B (wavelength 290− 315 nm). Pre­
vitamin D is then thermally isomerised to the more stable vitamin D3,
also known as cholecalciferol (Fig. 9). Keratinocytes are also capable of
converting vitamin D to its active metabolite, 1,25(OH)2 vitamin D via
cytochrome P450 enzymes (CYP27A1 and CYP27B1) (Umar et al.,
2018).
Vitamin E is a composite term for eight lipophilic molecules: four
tocopherols and four tocotrienols (Fig. 9). They have the chromanol ring
in common. It is a lipophilic vitamin that has antioxidant activity in skin.
S. Knox and N.M. O’Boyle
Fig. 9. Chemical structures of vitamins D2, D3 and E. Vitamin E refers to eight
different compounds, four based on the tocopherol scaffold and four based on
the tocotrienol scaffold.
2.3. Sebaceous gland lipids
In addition to the three main lipid classes (ceramides, fatty acids and
cholesterol), other lipids known as skin surface lipids are present on the
SC. These are either epidermal or sebaceous in origin, with composition
varying depending on anatomical location. According to lipidomic
analysis of the skin, supplementary lipids are supplied to the SC via
sebum. Sebum is a lipid-rich substance containing squalene, TAGs and
wax esters, produced in the sebaceous glands (Fig. 10) (De Luca and
Valacchi, 2010; Pappas, 2009; Smith and Thiboutot, 2008). Several of
these lipids, notably squalene and wax esters, are only characterised in
sebum at present and not at any other anatomical location. Sebum also
delivers both glycerol and vitamin E to the SC which hydrate the skin’s
surface (Yen et al., 2005). It is unevenly distributed across the skin with
Fig. 10. Lipid composition of human sebum by dry weight as a percentage of
total lipid content. Percentage contribution (mean values) of triacylglycerols
(TAGs) (45 %), wax esters (25 %), squalene (12 %), non-esterified fatty acids
(NEFAs) (10 %), cholesterol and sterol esters (10 %), and diacylglycerols
(DAGs) (2 %). Adapted from Ref. Pappas (2009); Picardo et al. (2009).
8
Chemistry and Physics of Lipids 236 (2021) 105055
the highest concentrations at the forehead, upper chest, and dorsum.
The density of sebaceous glands varies by body site, which in turn in­
fluences the SC lipidome. For example, sebaceous NEFA were increased
in areas with a high density of sebaceous glands, whilst epidermal NEFA
were decreased (Ludovici et al., 2018). Sebum moisturises and protects
the skin by acting as a barrier against bacteria and other xenobiotics, and
there is emerging evidence for an immunomodulatory role. In many
different skin diseases including acne, atopic and seborrheic dermatitis,
sebum composition undergoes significant changes, as reviewed recently
(Lovászi et al., 2017).
The predominant lipid subclass in sebum are the TAGs. High per­
formance liquid chromatography (HPLC) combined with mass spec­
trometry identified 95 families of TAGs alongside 29 families of DAGs
(Camera et al., 2010). In the same study, the majority of wax esters were
shown to contain a fatty acid C16:1 acyl group.
The polyunsaturated hydrocarbon squalene (Fig. 11) is an important
component of sebum (10–15 %) and 50− 125 mg (variation due to age,
gender, ethnicity) of sebum is present on the face daily (Pham et al.,
2015). Squalene is formed through the condensation of two molecules of
farnesyl pyrophosphate, catalysed by squalene synthase.
NEFAs make up a significant proportion of sebum, with the most
common NEFAs shown in Fig. 4b. NEFAs in sebum have a chain length
ranging between 12 and 30 carbons with a degree of unsaturation be­
tween 0 and 6 double bonds (Camera et al., 2010; Ní Raghallaigh et al.,
2012). NEFA are essential for the structural integrity of skin and serve as
endogenous antiseptics. When secreted in sebum from the sebaceous
glands, NEFA have ‘self-sterilizing’ properties on the surface of the skin.
Sapienic acid, an isomer of palmitoleic acid, is a unique sebaceous
monounsaturated fatty acid found only in sebum, where it comprises
over 20 % of the total fatty acid content (Figs. 4 and 11). In one study of
sebaceous NEFA composition (n = 24), there were statistically signifi­
cant differences between sexes in the amount of sebaceous fatty acids,
underlining the myriad of factors that can influence skin composition
(Ní Raghallaigh et al., 2012). Sebaceous NEFA were increased in areas
with high sebaceous gland density (Ludovici et al., 2018).
3. Lipids in skin diseases and disorders
Common and rare skin conditions alike are linked to alterations in
skin lipid composition and metabolism including atopic dermatitis,
psoriasis, acne vulgaris, lamellar ichthyosis, recessive X-linked ich­
thyosis, bullous ichthyosiform erythroderma (Paige et al., 1994), type 2
Gaucher disease, Sjorgen-Larsson syndrome, essential free fatty acid
deficiency, aged dry skin, and hypohidrotic ectodermal dysplasia (Sahle
et al., 2015). However, links between skin disorders and specific lipid
concentrations can be difficult to define due to the diverse range of lipid
molecules that are attainable, particularly ceramides (Coderch et al.,
2003). There are also other skin components, mainly water and proteins,
to consider. Despite skin variability, sampling and analytical challenges,
it is clear that there are significant changes in lipids in skin disease.
Previous excellent reviews on lipids in the SC of diseased skin are
Fig. 11. (A) Chemical structure of the sebum lipid, squalene; (B) Mono­
unsaturated fatty acid isomers palmitoleic acid and sapienic acid.
S. Knox and N.M. O’Boyle Chemistry and Physics of Lipids 236 (2021) 105055

Table 3
Summary of changes to skin or serum lipids in skin diseases and conditions. Changes are to skin lipids of involved (diseased) skin unless indicated otherwise. SSL = skin
surface lipids.
Skin Disease/Condition Ceramides and Derivatives Other Skin Lipids

General trends: General trends:

↓ Total ceramides (Li et al., 2016; Imokawa et al., 1991;
Matsumoto et al., 1999)
↑ Short-chain fatty acids
↑ Short-chain ceramides
↓ Long-chain ceramides
Specific trends (increased levels): Specific trends:
↑ C34 short chain (Janssens et al., 2012)
↑ CER[NS] (children) (Shen et al., 2018)
↑ CER[AS] (children) (Shen et al., 2018)
↑ CER[NS] (Berdyshev et al., 2018)
↑ CER36 [NS] (Agrawal et al., 2018) (male and female)
Atopic Dermatitis ↑ CER36 [NdS] (Agrawal et al., 2018) (male and female)
↑ CER [S]/[dS] (Toncic et al., 2020)
↑ Glucosylceramide (Toncic et al., 2020)
↑ esterified C18:1 fatty acids (oleate) of acylceramides ( ↑ 14:0− 22:0 lysophosphatidylcholines (Berdyshev et al., 2018)
Yamamoto et al., 1991)
↑ Sphingomyelins (Berdyshev et al., 2018)
↑ Sphingosine (Toncic et al., 2020)
↑ Sphinganine (Toncic et al., 2020)
Specific trends (decreased levels):
↓ Sphingosine (Arikawa et al., 2002)
↓ Sphingosine (uninvolved skin) (Arikawa et al., 2002)
↓ Acylceramides (Yamamoto et al., 1991)
↓ Fatty acids, e.g. arachidic (20:0), α-linolenic (18:3n-3), and total n-3 PUFA (
↓ Total ceramides (blood serum) (Myśliwiec et al., 2017)
Mysliwiec et al., 2019)
↓ CER[EOS] (Cer-1) (SC) (Motta et al., 1994) ↑ total epidermal lipids (Pietrzak et al., 2010)
↑ Sphingosine (Moon et al., 2013; Checa et al., 2015) ↑ epidermal phospholipids (Pietrzak et al., 2010)
↑ Sphinganine (Moon et al., 2013; Checa et al., 2015) ↑ epidermal TAGs (Pietrzak et al., 2010)
Psoriasis
↑ Sphingosine-1-phosphate (Checa et al., 2015) ↑ epidermal cholesterol (Pietrzak et al., 2010)
↑ Sphingosine-1-phosphate (blood serum) (Myśliwiec et al.,
↑ total phospholipids (Tsambaos et al., 1977; Tsambaos and Mahrle, 1979)
2017; Kozłowska et al., 2019)
↑ Ceramides C12:0, C16:0, C18:0, C18:1, C24:0 and C24:1 (Checa
↓ total phospholipids (epidermis) (Gerstein, 1963)
et al., 2015)
Rosacea (PPR) ↓ Long chain saturated fatty acids (sebum) (Ní Raghallaigh et al., 2012)
↑ DAGs (sebum, juveniles) (Camera et al., 2016)
↑ Squalene (Pappas et al., 2009)
↑ Fatty acids (Camera et al., 2016; Pappas et al., 2009)
↑ Unsaturated NEFAs (Zhou et al., 2018)
↓ Saturated NEFAs (Zhou et al., 2018)
Acne ↓ Average ceramide chain length (Zhou et al., 2018)
↑ Cholesterol (SSL) (Zhou et al., 2018)
↑ Wax esters (SSL) (Zhou et al., 2018)
↑ Squalene-related compounds
(triterpenes)(SSL) (Zhou et al., 2018)
↓ Linoleic acid (SSL) (Zhou et al., 2018)
Recessive X-Linked
↑ Cholesterol sulfate:cholesterol ratio (Elias et al., 1984)
Ichthyosis
↑ Total ceramides (Paige et al., 1994)
Lamellar Ichthyosis ↓ Ceramide 1 (acyl) (Paige et al., 1994) ↓ Fatty acids (Lavrijsen et al., 1995)
⨯ ceramides with very long acyl chains (C26 - C34)
↓ Total ceramides ↓ NEFA chain lengths (van Smeden et al., 2014c)
↑ Short-chain ceramides ↑ levels of monounsaturated fatty acids (van Smeden et al., 2014c)
↓ acyl-CERs (subgroup of patients) ↑ NEFA C20:0 and C21:0 (van Smeden et al., 2014c)
Netherton Syndrome ↓ CER [NP] (van Smeden et al., 2020) ↓ Decrease in NEFAs C24:0, C25:0, and C26:0 (van Smeden et al., 2014c)
↑ C34 CERs of subclasses
[NS], [AS], and [AH] (van Smeden et al., 2020, 2014c)
↓ very long CERs [EO] (van Smeden et al., 2020)
Sjogren-Larsson
↓ Ceramides 1 and 6 (acyl) (Paige et al., 1994)
syndrome
↓ Total ceramides (non-involved skin) (Kim et al., 2017)
Allergic Contact
↓ Ceramides [AH], [NH], [NP], [AP], [NS], [AS] (non-involved
Dermatitis
skin) (Kim et al., 2017)
Hidradenitis ↑ shorter, odd-chain fatty acids (C15:0, C13:0, etc.)(region surrounding the hair
↑galabiosyl-/lactosylceramides (dermis)
Suppurativa follicle and apocrine sweat gland)

available from Harding in 2004 (Harding, 2004) and Sahle in 2015
(Sahle et al., 2015). Here, we provide an update on recent literature
from 2015 to the present concerning skin lipids in several skin diseases
and disorders, focusing on the SC, epidermis (full-thickness or viable as
indicated) and sebum. Table 3 presents a summary of the results dis­
cussed in the following sections. Common trends across different skin
diseases are notable, e.g. decreases in fatty acid chain length in diseased
skin, or decreases in total ceramide concentrations.
3.1. Atopic dermatitis
More is known about lipids in atopic dermatitis (AD) than any other
skin disease. Evidence suggests that there is a strong association between
the composition of lipids in the skin and barrier abnormalities such as
those found in AD (Table 3) (Elias, 2014; Imokawa, 2001). Total skin
lipids, measured at three anatomical locations, were significantly lower
in patients with AD compared to control (Sator et al., 2003). The lipid:

9
S. Knox and N.M. O’Boyle Chemistry and Physics of Lipids 236 (2021) 105055

protein ratio is also decreased in both involved and uninvolved skin of Table 4
AD patients (Janssens et al., 2014). A previous book chapter by Jensen Lipids in stratum corneum from healthy subjects (n = 7) compared to unin­
(Jensen et al., 2006) and subsequent reviews by Jungersted in 2008 volved skin in patients with atopic dermatitis (n = 7) or psoriasis (n = 6),
(Jungersted et al., 2008) and Elias in 2014 (Elias, 2014) summarise the expressed as percentages of the total lipids (ceramides + cholesterol + non-
state-of-the-art at those times. More recently, Bhattacharya et al. esterified fatty acids, NEFA) (Farwanah et al., 2005b).
(2019a) have reviewed lipid mediators of AD and the transcriptional Skin type Ceramides Cholesterol NEFA
regulation of genes associated with skin lipid metabolism in the context Healthy 53.1 ± 6.3 17.0 ± 2.9 30.0 ± 5.1
of AD. Atopic Dermatitis (uninvolved skin) 48.7 ± 5.5 19.2 ± 2.4 32.1 ± 5.4
Ceramides were one of the first lipid subclasses to be associated with Psoriasis (uninvolved skin) 50.6 ± 10 18.4 ± 5.9 31.0 ± 11.7
AD and deficiency in the barrier function of the skin (Bhattacharya et al.,
2019b). Numerous studies have found a significant reduction in the total
3.2. Psoriasis
amount of SC ceramides when patients with lesional and non-lesional
AD are compared to patients with healthy skin of the same age (Kim
As with AD, ceramides are the most commonly studied lipid subclass
et al., 2017). The decrease in ceramides disturbs the highly ordered lipid
in psoriasis. Motta et al. investigated the distribution of ceramides is
lamellae, upsetting the barrier function of the skin. Shen et al. conducted
psoriatic scale versus healthy SC (Motta et al., 1994). It was concluded
an observational study on children with AD and found that the ceramide
that the reduction of the ceramide lipids on the surface of skin was
subclasses [AS] and [NS] were increased in diseased skin (Shen et al.,
related to the dysfunction of the skin barrier in psoriatic patients.
2018). Two other studies noted altered ceramide levels in AD indepen­
Sphingoid bases are also altered in psoriasis as reviewed comprehen­
dent of filaggrin mutations (Jungersted et al., 2010; Angelova-Fischer
sively in 2016 (Borodzicz et al., 2016). This is, at least partially, a result
et al., 2011). More recently, studies of ceramides in vitro using model
of altered metabolism of sphingolipids (Bocheńska and Gabig-Cimińska,
membranes showed altered skin architecture depending on the relative
2020). Higher levels of sphingosine and sphinganine were found in
composition of the membranes (Opálka et al., 2020). Glucosylceramide
psoriatic lesions compared to non-lesional full-thickness epidermis from
and free sphingoid bases are also increased in lesional skin of AD sub­
the same patients (Moon et al., 2013). Serum ceramide and sphingosine
jects (Toncic et al., 2020). A contrasting finding is a decrease in sphin­
concentrations in patients with psoriasis have been determined in
gosine levels in both uninvolved and involved SC of patients with AD
several studies. Blood plasma concentrations of [NS] sphingolipids
compared with healthy controls, possibly as a result of decreased cer­
[including sphingosine, sphingosine-1-phosphate (S1P), sphinganine
amide levels and decreased metabolism by acid ceramidase (Arikawa
and Spa1P] were significantly elevated in severe psoriasis compared
et al., 2002). Sebum lipid mediators are affected in AD, e.g. ceramides
with healthy controls and mild psoriasis. Very significant differences in
C36 [NS] and [NDS] (Agrawal et al., 2018). Treatment of AD with a
sphingolipid profiles from lesional skin of patients with severe psoriasis
synthetic pseudoceramide reduced skin symptoms and increased hy­
were also determined, compared to non-lesional skin and healthy con­
dration in the skin, providing further indications of the involvement of
trols. Skin in this study was taken using a 4 mm punch biopsy and not
ceramides in AD (Ishida et al., 2020). Daily full-body application of an
separated so likely represents a mixture of epidermis and dermis.
emollient with ceramide and amino acids may improve outcomes in
Changes included significantly increased levels of the ceramides C12:0,
infants at high-risk of AD (McClanahan et al., 2019).
C16:0, C18:0, C18:1, C24:0 and C24:1 (Checa et al., 2015). More
Ceramides are not the only lipid subclass to be affected; n3/n6-
recently, extracted keratinocytes from full-thickness human epidermis
polyunsaturated fatty acid (PUFA) and metabolite ratios were lower in
and fibroblasts from human dermis were studied. Samples were from
the skin of patients with AD (Töröcsik et al., 2019). It has been consis­
patients with untreated psoriasis (n = 6). Six of the identified ceramide
tently shown that patients with AD have a higher proportion of
subclasses (CER[NS], CER[NP], CER[AS], CER[ADS], CER[AP] and CER
short-chain lipids and a lower proportion of longer-chain lipids,
[EOS]) were expressed at higher levels in keratinocytes from subjects
including fatty acids and ceramides. Janssens et al. studied the alter­
with psoriasis, than control, and CER[NDS] tended to be expressed at
ations that occurred within the ceramide subclasses and the corre­
lower levels than control healthy subjects. In the case of fibroblasts,
sponding aliphatic chain length when skin permeability was reduced
significant differences were observed, mainly in the three ceramide
during disease (Janssens et al., 2012). It was found that there was an
classes (CER[AS], CER[ADS] and CER[EOS]) (Łuczaj et al., 2020).
increase in the proportion of C34 short chain ceramides. The reduction
Another study found that total serum concentration of ceramide in pe­
of the chain length is believed to contribute to disrupted lipid organi­
ripheral blood samples was significantly decreased alongside increased
sation and therefore, increase permeability of the skin during disease.
levels of the sphingolipid (S1P) in psoriatic patients compared to healthy
Recently, increased amount of shorter chain lipids including [NS]
controls (Myśliwiec et al., 2017). In a further study, serum concentra­
ceramides, sphingomyelins, and C14:0–22:0 lysophosphatidylcholines
tions of S1P were higher in blood samples from patients with psoriasis
were noted in AD subjects compared to healthy controls (Berdyshev
compared to healthy subjects, regardless of patient weight (Kozłowska
et al., 2018). Altered expression of key enzymes involved in the
et al., 2019). Hence, the general trend is higher sphingolipid concen­
biosynthesis of fatty acids and ceramides, e.g. stearoyl CoA desaturase
trations in psoriasis. It is important to take disease severity into account
(SCD) and elongase 1 (ELOVL1), at least partially contribute to these
when analysing data, e.g. by using the PASI score. Total serum ceramide
changes in composition (Danso et al., 2017). Lipid mediators including
concentrations were unchanged when levels in patients with psoriasis
prostanoids and leukotrienes are also elevated in AD (Honda and
were compared to healthy controls (Kozłowska et al., 2019).
Kabashima, 2019).
Fatty acids are also affected in psoriasis. The serum concentrations of
Farwanah et al. analysed the composition of lipids in the SC in pa­
10 (of 14 measured) fatty acids in blood samples from patients with
tients with healthy skin versus “uninvolved skin” from patients with AD
psoriasis were lower than those in healthy controls, with a majority of
using AMD-HPTLC and densitometry (Farwanah et al., 2005b). No sig­
male subjects. Examples were differences in arachidic (20:0), α-linolenic
nificant differences in the three main lipid classes, ceramides, choles­
(C18:3, n-3), total n-3 polyunsaturated fatty acids and total n-6 poly­
terol, and fatty acids were noted (Table 4); hence, the “healthy” or
unsaturated fatty acids (Mysliwiec et al., 2019).
unaffected SC of the patient with AD was comparable to that of an in­
Other studies found an increase in the total lipids, phospholipids,
dividual with no skin conditions. A more recent study reports signifi­
TAGs and cholesterol in full-thickness epidermis of patients suffering
cantly different ratios of specific lipids, including Cer [NP]/[NS],
from psoriasis (Pietrzak et al., 2010). These findings are in agreement
between non-lesional SC of AD patients and SC of healthy control sub­
with two earlier works that characterised increased total phospholipids
jects (Yokose et al., 2020).
in full-thickness epidermis from psoriatic skin by thin layer

10
S. Knox and N.M. O’Boyle
chromatography (Tsambaos et al., 1977; Tsambaos and Mahrle, 1979).
In severe cases, the proportion of esterified fatty acid chains decrease in
the epidermis. In contrast, an early study from 1963 found a significant
decrease in the concentration of total phospholipids in full-thickness
epidermis of patients with psoriasis (Gerstein, 1963).
Farwanah et al. analysed the composition of lipids in the SC in pa­
tients with healthy skin versus patients with psoriasis using AMD-HPTLC
and densitometry (Farwanah et al., 2005b). There were no statistically
significant differences to the lipid content in the SC of uninvolved skin
from psoriasis patients compared to healthy skin (Table 4).
3.3. Acne
Acne vulgaris is a common skin condition that usually begins in
puberty. Acne has been associated with lipids for decades (Ayres and
Mihan, 1978) and is characterised by overproduction of sebum in the
sebaceous glands leading to the formation of comedones and pus-filled
spots, as previously reviewed (Ottaviani et al., 2010; Clayton et al.,
2019). The role of sebum in the pathogenesis of acne also has been
recently reviewed (Li et al., 2017). There is debate over the role of
certain sebum components, rather than total sebum levels, as a causative
factor in acne. Fig. 4B shows typical sebum NEFA composition in healthy
skin. Sebum composition is markedly different in adolescents with acne
compared to healthy skin. DAGs in particular were abundant in the
sebum of juvenile patients with acne, with 16 of 17 DAGs showing
elevated levels (Camera et al., 2016). Squalene and NEFAs were also
expressed at higher levels in sebum of skin affected by acne (Camera
et al., 2016; Pappas et al., 2009). In acne, TAGs are lysed to NEFAs by
oxygen and microorganisms (Zouboulis et al., 2014). Interestingly, a
reactive hydroperoxide byproduct of squalene peroxidation, squalene
monohydroperoxide (SqMOOH), is comedogenic (Chiba et al., 2000).
Considering the recent characterisation of six specific SqMOOH isomers
(Shimizu et al., 2018), further investigation into the products of lipid
metabolism could yield insights into the molecular alterations in acne.
Aside from sebum, other skin surface lipids (SSL) are altered in acne.
Facial SSL sampled from young male patients with acne had significantly
higher levels of phosphatidylserines, a reduction in the average chain
length of ceramides, an increase in unsaturated NEFAs and a decrease in
saturated NEFAs (Zhou et al., 2018). More recent work from the same
group investigated SSL in acne of infants and adolescents. Infantile acne
(aged 1–4 months) was associated with higher levels of squalene,
NEFAs, and TAGs, as well as shorter average ceramide chain lengths.
The relative amount of ceramides was also increased (Zhou et al.,
2020a). The relative average content of TAGs, DAGs, NEFA, and
ceramides significantly increased from mild to moderate adolescent
acne (Zhou et al., 2020b).
3.4. Rosacea
There is, to the best of our knowledge, only one study that in­
vestigates the role of skin lipids in rosacea. Ní Raghallaigh et al. (2012)
showed that patients with papulopustular rosacea (PPR) have an
abnormal sebaceous fatty acid composition. Myristic acid (C14:0) was
increased in PRR whilst levels of longer chain saturated fatty acids
(including C20:0, C22:0, C23:0 C24:0) were reduced (Table 3). Further
research in this field is warranted.
3.5. Hereditary ichthyoses
Ichthyosis is a genetic or acquired skin condition that causes
persistent and widespread scaling of the skin. It is a disorder associated
with altered lipid metabolism in the skin, regardless of the underlying
genetic cause. Many genes associated with ichthyosis are involved in the
barrier function of the SC, e.g. fatty acid transport protein 4 (FATP4)
(Lin et al., 2019), short-chain dehydrogenase/reductase family 9C
member 7 (SDR9C7) (Takeichi et al., 2020) and others previously
11
Chemistry and Physics of Lipids 236 (2021) 105055
reviewed (Akiyama, 2017).
Recessive X-linked ichthyosis occurs in males only and is charac­
terised by a deficiency in enzymatic steroid sulfatase activity. This
causes increased levels of cholesterol sulfate (Fig. 3), leading to clinical
symptoms such as excessive scaling (Elias, 2014). Cholesterol sulfate
accumulates in the SC causing abnormalities in epidermal differentia­
tion and permeability barrier. In X-linked ichthyosis disorder, the
cholesterol:cholesterol sulfate ratio in the SC is 1:1 compared to a usual
ratio of between 5:1 and 10:1 (Elias et al., 1984).
Autosomal recessive congenital ichthyoses are rare inherited skin
disorders. Patients with lamellar ichthyosis have increased total
ceramides, decreased ceramide 1 (Paige et al., 1994), reduced NEFAs
(FFAs), FFA:human ceramide and FFA:cholesterol molar ratios (Lav­
rijsen et al., 1995). Skin lipid organisation is also altered; the hexagonal
lattice in these patients predominates at the expense of the ortho­
rhombic sublattice (Pilgram et al., 2001). Synthesis of very long acyl
chain ceramides (C26 – C36) is impaired in patients with this condition,
due in part to inactivation of the CerS3 ceramide synthase enzyme (Eckl
et al., 2013). Such long chain ceramides are crucial for optimal barrier
function.
Netherton syndrome is a genetic condition in which increased serine
protease activity leads to impaired barrier function and skin inflam­
mation. There are lower levels of saturated FFAs and a higher level of
monounsaturated fatty acids in the SC of patients with Netherton syn­
drome compared with SC of controls, with a shift to shorter fatty acid
chains. This leads to increased disorder in lipid organization (van
Smeden et al., 2014c). There are increased levels of ceramide [NP] and
reduced levels of ceramides [AS] and [NS]. There are also decreased
levels of very long [EO] ceramides (van Smeden et al., 2020). Changes in
two key enzymes in ceramide biosynthesis, β-glucocerebrosidase (GBA)
and acid-sphingomyelinase (ASM), play a role in altered ceramide
composition and clinical presentation of the syndrome (van Smeden
et al., 2020). Likewise, patients with Sjogren-Larsson syndrome have
reduced levels of acyl-ceramides (ceramides 1 and 6) (Paige et al.,
1994).
3.6. Allergic and irritant contact dermatitis
Irritant and allergic contact dermatitis (ICD and ACD) are types of
eczema that develop upon regular or repeated exposure to an irritant or
allergen, respectively, resulting in pruritis, blisters and dry skin at the
site of contact (Novak-Bilić et al., 2018). Human full-thickness skin
(epidermis and dermis) releases linoleic and arachidonic acid metabo­
lites following exposure to chemical irritants (van de Sandt et al., 1995).
15-Hydroxyeicosatetraenoic acid (15-HETE) and 13-hydroxyoctadeca­
dienoic acid (13-HODE) were the dominant metabolites, with
12-hydroxyeicosatetraenoic acid (12-HETE) being the most sensitive
marker to chemical irritants. In the same study, human skin cultures
released ω-6 oxygenase products of arachidonic acid and linoleic acid
after exposure to irritants.
Little is known about skin lipids and ACD. Total ceramides are
reduced in the SC of non-lesional skin of patients with ACD, alongside a
decrease in overall ceramide chain length (Table 3). There were no
differences in TAG and NEFA levels (Kim et al., 2017). Schwarz et al.
studied the effects of short chain fatty acids, formed by commensal skin
bacteria, on the activation of resident skin T cells (Schwarz et al., 2017).
When sodium butyrate was injected or topically applied to
hapten-sensitized mice, the elicitation phase of the contact hypersensi­
tivity reaction was reduced and CD4+CD25− nonregulatory human T
cells suppressed an inflammatory reaction. This indicates a potential
role for fatty acids as mediators in ACD. Barrier dysfunction skin con­
ditions occur from alternative pathophysiology and by determining the
changes to skin lipids that occur in ICD and ACD, new insights into their
aetiology may be gained.
S. Knox and N.M. O’Boyle
3.7. Hidradenitis suppurativa
Limited research into skin lipid profiles in hidradenitis suppurativa
(HS) has been carried out. Enzymes involved in sphingolipid metabolism
are altered in HS, for example, decreased expression of enzymes
generating ceramides and sphingomyelin (Dany and Elston, 2017).
Levels of sphingolipids were not determined in that study, but subse­
quent work by Fincher et al. found higher levels of gal­
abiosyl-/lactosylceramides in the dermis of HS diseased tissue. TAGs
comprised of shorter, odd-chain fatty acids (C15:0, C13:0, etc.) were
also more abundant in HS tissue sampled from the region surrounding
the hair follicle and apocrine sweat gland (Fincher et al., 2019). More
recently, a study of 46 PUFAs in samples from HS indicated elevated
levels of ten lipids, including 5,6-dihydroxyeicosatetraenoic acid,
compared to control. These were mostly 5-lipoxygenase‒derived me­
tabolites. Levels of four PUFAs including docosahexaenoic acid and
eicosapentaenoic acid were decreased (Penno et al., 2020). Further
research into lipid involvement in this chronic, inflammatory skin dis­
ease is warranted.
4. Summary
Skin lipid composition and structure is an important part of the skin
barrier, and it is unsurprising that it is affected in skin diseases and
disorders. The general trend is for decreased lipid content and shorter
lipid chains in affected skin, though uninvolved skin in patients with
skin disease can also be significantly different compared to healthy skin
in unaffected control subjects. Many skin diseases present with similar
trends in skin lipid profiles, potentially limiting their use as biomarkers
unless disease-specific differences can be found. One of the key chal­
lenges for the future will be to convert the findings into clinically useful
tools for prevention, diagnosis and treatment of skin diseases. Analytical
methods for lipidomics are improving rapidly and will be key for further
understanding of the role of lipids in skin disease. Future research
should also investigate different patient cohorts, e.g. gender, age, and
race, which are important factors to consider.
Author contributions
NMO’B and SK researched the material, wrote drafts of the manu­
script, and approved the manuscript for submission.
Declaration of Competing Interest
No conflicts of interest for this work.
Acknowledgements
Funding for this project was kindly provided by an Analytical
Chemistry Trust Fund CAMS-UK Fellowship (NMO’B/Ref:600310/07).
We gratefully acknowledge Mr. Cian O’Boyle (cian.oboyle.2013@gmail.
com) for Fig. 1 graphics.
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