Stratum comeum barrier 
Review 
IMPORTANCE OF EPIDERMAL LIPIDS FOR 
PROPER FUNCTIONING OF THE STRATUM 
CORNEUM BARRIER 
A. Kansky and J. Kristl 
SUMMARY 
Proper structure of stratum corneum (SC) is important for regulation of vita! biologic functions as are 
protection from penetration of foreign substances through the skin, protection from UV rays, abnormal 
transepidermal water loss (TEWL), protection from injuries, or smooth shedding of corneocytes. Two systems, 
the epidermal lipids (interstitial lipids of SC) and the corneocyte cell envelopes (eE) are primarily responsible 
for the so-called barrier function. Lipids reach the se through the secretion of lamellar (Odland) bodies 
situated in the granular layer, while the eE are being formed from loricrin, involucrin as well as from other 
protein precursors. Barrier function is impaired in a number of skin disorders, e.g. chronic eczema, atopic 
dermatitis, ichthyoses, aged skin as well as in others. Clinical tests in humans and animal experiments are 
teaching us that the barrier function may be restored more quickly by applying ointments and creams 
containing adequate mixtures of lipids. 
KEY WORDS 
barrier function, stratum comeum, epidermal lipids, comified celi envelope 
INTRODUCTION 
Dry skin and associated metabolic abnormalities 
are key symptoms in a number of skin disorders: 
cutis senilis, dermatitis atopica, contact dermatitis, 
ichthyoses, and others. A primary factor causing dry 
skin is the increased evaporation of water through 
the epidermis (transepidermal water loss, TEWL). 
Proper functioning of stratum corneum (SC) is 
important for a number of processes, e.g. regulation 
of TEWL, inhibition of penetration of foreign substances 
through the skin, protection against UV irradiation, 
acta dennatovenerologica A.P.A. Vol 7, 98, No 1 
cooperation in the normal process of keratinization 
as well as adhesion and physiologic desquamation of 
korneocytes. This so-called barrier function depends 
on the integrity of the se, specially on its content 
of lipids and on a properly structured cornified cell 
envelope (eE). TEWL can be measured and thus 
represents a model for assessing the barrier function 
of the skin. 
The present is a rather simplified attempt to 
explain shortly and in a way understandable to 
clinicians the essentially very complicated premises 
for an adequate barrier function. 
3 
Stratum comeum barrier 
EPIDERMAL LIPIDS 
Skin surface lipids derive in principles from two 
sources: firstly, lipids produced by sebaceous glands 
and secondly epidermal lipids which are an important 
constitutive material of the epidermal cells ( cell 
membranes) and are mainly responsible for maintaining 
the barrier homeostasis. 
Epidermal lipids are built up from a few basic 
substances which can be arbitrarily differentiated 
into backbone substances e.g. glycerol, sterols, 
sphingosine and ligands e.g. fatty acids, glucose, 
sulfuric and phosphoric acids. Ligands are esterified 
to the functional groups of the backbones in various 
combinations. 
For didactic purposes epidermal lipids can be 
divided into three classes (1): 
l. simple lipids like n-alkanes, fatty acids, triglycerols, 
phospholipids 
2. sphingolipids are built up from the backbone 
sphingosine and the ligands fatty acid and glucose 
( ceramides and glucosylceramides) 
3. sterols are synthesized by a different pathway than 
the other two classes. Free sterols, sterol esters, and 
cholesterol sulfate are characteristic compounds of 
epidermal lipids. Squalene, an intermediate in sterol 
synthesis, is a nonpolar sebaceous lipid on the skin 
surfaces, but it is only a minor component of 
epidermal lipids. Figure l. 
In parallel to the differentiation of keratins from 
basal layer to the stratum corneum, the composition 
of epidermal lipids also undergoes changes (1). In 
the basal layer polar lipids, e.g. phospholipids and 
glycosylceramides, are expressed in addition to neutral 
lipids, while nonpolar lipids as neutral lipids, ceramides 
and cholesterol are the main components of the 
outer SC. Actually, the glycosylceramides increase 
up to stratum granulosum (SG) and then rapidly 
decrease due to the activity of the glycosidases. 
eholesterol sulfate also increases up to SG and then 
diminishes in response to the activity of steroid 
sulfatase. It may be concluded that some essential 
changes and events occur at the interface between 
the SG and se providing the biochemical alterations 
as well the deposition of the lipids into the intercellular 
space (1,2,3). Figure 2. 
In living epidermal cells the lipids are mainly 
localized in the cell membranes. In the SG they are 
present in the lamellar bodies (Odland bodies, LB) 
4 
CH2 - O - fatty acid 
1 
fatty acid - CH O 
1 II 
CH2-o-r-OH 
OH 
__ cholnie . 
,c-:::::.-- etanolamine 
•------ serine 
--............_ inosital 
phospholipid 
NH2 
1 
CH 
HOH C/ 'cH NVVV0/V 
2 1 
OH 
sphingosin 
o 
HN ~CH3 
1 
CH A.AAAAAA1CH3 
HOH C/ '-CH' v v v v v v v 
2 1 
OH 
ceramide 
o 
~ 
CH2OH H~ CH3 
O'-../CH ......_ N0/VVVVCH3 
CH 
1 
HO OH 
OH 
glycosilceramide 
Figure l. Chemical formulas of some epidermal lipids 
and in the se within the intercellular spaces as 
parallel lamellar structures (intercellular lipids ). LB 
are specialized lipid storage or secretory organelles 
that are surrounded by a membrane and have a core 
composed of multilamellar membranes. The current 
concept represents se as a two component system in 
which cells ( corneocytes) are compared to bricks 
and intercellular lipids to mortar ( 4). The intercellular 
lipids are mainly expressed as lamellar bilayer structures 
by electron microscopy, using the ruthenium tetroxide 
postfixation. They are mainly responsible for controlling 
acta dermatovenerologica A.P.A. Vol 7, 98, No 1 
Stratum corneum barrier 
the penetration of exogenous substances through the 
skin as well as for controlling the TEWL. The 
intercellular lipids of se derive mostly through the 
secretion of the LB. Figure 3. 
The best-investigated LBs are produced by pneumo-
cyte II cells in the Jung alveoli where they provide 
the surfactant system (5). 
Under experimental conditions the barrier function 
may be impaired or eliminated by tape stripping or 
extraction with solvents. In the young, the epidermis 
barrier perturbation results in a homeostatic response, 
which includes: l. immediate secretion of already 
existing lamellar bodies, 2. new formation and ongoing 
secretion of lamellar bodies. This secretory response 
is fueled by increased synthesis of cholesterol, fatty 
acids, and ceramides. Increased levels of 3-hydroxy-
POLAR 
LIPID$ 
(mostly in lamellar bodies) 
ENZVMES 
B-glycocerebrosidase 
phospholipase A 
sphingomyelinase 
NONPOLAR 
LIPID$ 
(mostly in the 
intercellular space) 
fatty acids 
ceramides 
cholesterol 
STRATUM GRANULOSUM STRATUM CORNEUM 
Legend: 
polar lipids •)~( -+HE---lME- nonpolar lipids ----
Figure 2. Distribution of lipid fractions in stratum 
granulosum and stratum comeum 
acta dermatovenerologica A.P.A. Vol 7, 98, No 1 
3 methylglutaryl-coenzyme A reductase (HMG-eoA 
red) which is the rate-limiting enzyme of cholesterolo-
genesis, as well as an increase in the activities of 
acetyl eoA carboxylase and fatty acids synthase 
which are the rate-limiting enzymes of fatty acids 
synthesis, are responsible for the restitution of the 
intercellular lipids (6). 
In aged persons the se displays a globa! reduction 
in lipids with reduced number of extracellular bilayers. 
The permeability of the barrier is adequate under 
basal (normal) conditions, but when challenged acutely, 
its integrity and recovery are impaired in both aged 
human and aged murine skin (7). In a similar way 
the barrier recovery was delayed in aged mice after 
a chronic perturbation due to a reduced synthesis of 
cholesterol in response to a decreased activity of 
HMG eo A red (8). 
CORNIFIED CELL ENVELOPE 
The fina! stage of mammalian epidermal cell 
differentiation is the formation of the cornified cell 
envelope (eE), which is a 15 nm thick cross-linked 
sheath of proteins, on the inner surface of the 
plasma membrane in keratinocytes of the stratum 
corneum (9,10). The eE is built from cross-linked 
glutamate and lysine isopeptides. The epidermal 
enzyme transglutaminase (TGM) plays an important 
role by catalyzing the calcium dependent cross-
linking of proteins. It seems that the assembly of eE 
from its precursors is a gradual and complex process, 
in which numerous components participate, contributing 
to its thickness and rigidity. The best-characterized 
components (precursors) are loricrin (LOR), involucrin 
(INV) and the small prolin-rich proteins (SPRPs), 
all of them encoded by genes mapping to a region 
of chromosome lq 21, known as epidermal differen-
tiation complex (EDC) (10). 
Other known eE precursor proteins, which map 
to the same EDe region, are profilaggrin (proteo-
Iytically processed into filaggrin and serves as a 
matrix for packing intermediate filaments inside the 
corneocytes), trichohyaline and the small calcium 
binding proteins (SlO0Al-SlO0All). 
Desmosomal components as desmoplakin I, plako-
globin, envoplakin, plakophilin, desmocollin 3a/3b, 
desmoglein 3 are also active in structuring the eE. 
Further substances structuring the corneocyte and 
the eE are keratins (intermediate filaments), plasmogen 
activator inhibitor (PAI-2), annexin, as well as other 
less defined proteins (10,11). Figure 4. 
5 
Stratum comeum barrier 
The newly synthesized proteins undergo post 
synthetic fatty acid acylation resulting in attachment 
of fatty acids and ceramides derived from LB to the 
surface of the envelope (12) . 
A certain number of mutations involving the CE 
have been identified. Defects of TGMs causing 
lamellar ichthyosis (LI) are most frequently mentioned 
in the literature (13,14). A hereditary molecular 
defect of loricrin has also been described as the 
cause of the Vohwinkel syndrome (11). 
BARRIER FUNCTION 
If the stratum corneum is exposed to solvents, they 
dissolve the intercellular lipid structures and externally 
applied substances easily penetrate through it. At the 
body sites with a lower lipid content a better 
permeation of substances from outside and an increased 
TEWL may be observed. 
The regulation of TEWL was investigated years 
ago by Elias and his group (15) by introducing the 
essential fatty acids deficiency (EFAD) model in 
mice. Mice on an EFAD diet develop a hyperkeratosis 
of proliferative type and the LB appear largely 
empty as observed by electron microscopy. With a 
longer duration of this diet an increased TEWL was 
observed, which could be abolished by topical or 
8 
!'a. 
E 
::s 
III 
E..2 
::s ::s 
- C: jg f? 
III CI 
lamellar body 
(keratinosome) 
loricrin 
systemic application of linoleic acid, but this did not 
abolish the hyperproliferative state. Hyperproliferation 
was ameliorated by arachidonic acid, which did not 
influence the TEWL. It may be deducted from these 
animal experiments, l. that in pathological conditions 
in which barrier function is defective, such a condition 
can be provoked by an inadequate supply of essential 
fatty acids (linoleic acid), and 2. that a Jack in 
arachidonic acid can be the cause of epidermal 
hyperproliferation. Cholesterol also plays an important 
role in the proper functioning and maintenance of 
the epidermis and especially the horny layer. 
Diazocholesterol, which substance inhibits the 
cholesterol synthesis, induces in hairless mice a 
retention type hyperkeratosis, similar to that observed 
in x-linked recessive ichthyosis (16). The water-
binding capacity of stratum corneum depends mainly 
on the presence of ceramides and further lipids, 
though other natura! moisturizing factors, e.g. amino 
acids, sugars as well as other molecules are also 
important in this respect (17). It is not probable 
that the thin layer of emulsified fat on the skin 
surface, which results from the secretion of sebaceous 
glands (lipid film), has any great effect on the skin 
permeability. 
An increased TEWL compared to normal volunteers 
was reported in 3 patients with autosomal recessive 
erythrodermic lamellar ichthyosis (18). Such an 
observation was linked to a significant difference in 
involucrin 
keratohyalin granules 
containing profilaggrin 
Figure 3. Schematic presentation of human stratum comeum (brick and mortar model). lntercellular lipid 
bylayers are formed mostly through secretion of lamellar bodies. 
Legend: CE - comified cel! envelope, SC - stratum comeum, SG - stratum granulosum, IF - intermediate 
filaments 
6 acta dennatovenerologica A.P.A. Vol 7, 98, No 1 
Stratum comeum barrier 
the relative amounts of ceramides and other lipids. 
Abnormalities in epidermal lipid metabolism were 
also reported in-patients with atopic dermatitis (19) . 
EPIDERMAL LIPIDS IN 
DISORDERS OF KERATINIZATION 
Many of the pathogenic mechanisms triggering 
ichthyotic manifestations are stili not known. Following 
data result from molecular biology investigations 
and from analysis of lipids in the ichthyotic scales. 
Metabolic defects were best investigated in x-recessive 
SG 
cornified cell envelope (CE) 
TGM ====? ~ TGM 
LB 
desmoplakin 
desmocollin 
e 
keratohyalin granules 
loricrin 
involucrin 
SPRP 
S100A1-A11 
annexin 
desmoglein ~ CE percursos 
plakoglobin 
envoplakin 
Figure 4. Schematic presentation of the comified cel! 
envelope fonnation 
Legend: SC - stratum comeum, proFIL - profilaggrin, 
SG - stratum granulosum, SPRP - small protin rich 
proteins, CE - comified cel! envelope, SI 00AJ-All 
small calcium binding proteins, FIL - filaggrin, LB -
lamellar bodies, JF - lntennediate filaments, TGM -
transglutaminase 
acta dennatovenerologica A.P.A. Vol 7, 98, No 1 
ichthyosis vulgaris. In 1978, Shapiro et al have 
demonstrated the deficiency of the enzyme steroid 
sulfatase in cultured fibroblasts from such patients 
(20). Later on, such a defect was detected also in 
leukocytes and keratinocytes. As a consequence of 
the mentioned enzymatic deficiency cholesterol sulfate, 
which is normally catabolized to cholesterol, is 
increased in the outer se, while free cholesterol is 
decreased (21). This metabolic defect seems to be 
corresponsive for the adherence of ichthyotic scales. 
An increase in LDL cholesterol fraction in plasma 
has also been reported in these patients (22). 
Erythrodermia ichthyosiformis congenita ( erythro-
dermic lameli ar ichthyosis) is characterized by an 
increased content of n-alkanes in the horny layer 
(23), however such findings are not specific as they 
may be found also in neutral lipid storage diseases. 
In Refsum's syndrome the accumulation of phytanic 
acid due to a deficiency of phytanic acid alfa 
hydroxylase is responsible for the disturbed keratini-
zation. A linkage between nonerythrodermic lamellar 
ichthyosis and an increase of cholesterol in the 
epidermis is also probable (1). 
In harlequin ichthyosis there is an abnormal 
expression of keratins and fillagrin, in addition 
lamellar bodies and intercellular lipids within the 
se are absent or abnormal (24) . There is evidence 
that the harlequin ichthyosis belongs to a genetically 
heterogeneous group of disorders. 
In certain patients with lamellar ichthyosis (LI) 
deficiency in transglutaminase 1 (TGM-1) was detected. 
Permentier et al observed out of 23 families with 
severe LI a linkage to TGM-1 in 10 families, while 
in 13 such linkage did not exist (13). 
It was already mentioned that in the Vohwinkel 
syndrome (keratosis palmoplantaris mutilans) a 
molecular defect of loricrin has been reported (11 ). 
CONCLUSION 
A short review of certain pathological mechanisms 
contributing to the dry and to ichthyotic skin was 
attempted. Available experimental data suggest that 
an impaired barrier function is responsible for dry 
skin. Impaired metabolism of lipids in the skin and 
especially in the SC plays a major role in causing 
ichthyosis. Animal experiments as well as studies in 
human skin have provided many interesting data, it 
seems however that many more efforts are needed to 
solve ali the puzzles involved in the pathogenesis of 
ichthyosis. Some of the newly discovered facts 
7 
Stratum corneum barrier 
concerning the barrier function of SC represent a 
valuable contribution in treatment of certain skin 
diseases (25). Linoleic acid, ceramids, cholesterol, 
~nd some other ingredients are being currently 
mcorporated in commercially available topical prepa-
rations. 
ACKNOWLEDGEMENT 
The preparation of the manuscript was supported by 
the Slovenian Minist,y of Science and Technology; 
Grant No 13-9105. 
REFERENCES 
l. Meyer JCh. Metabolism oj epidermal lipids, Acta 
derm Jug 1991; 18: 205-16. 
2. Bortz IT, Wertz PW, Doiwing DT The origin of 
alkans f ound in the human skin surface lipids. J 
Invest Dermatol 1989; 93: 723-7. 
3. Williams ML. The ichthyosis - pathogenesis and 
prenatal diagnosis: a review of recent advances. 
Pediatr Dermatol 1983; 1: 1-24. 
4. Elias P. Epidermal lipids and desquamation. J 
Invest Dermatol 1983; 8: 44-9. 
5. Schmitz G, Muller G. Structure and function of 
lamellar bodies, lipid-protein complexes involved in 
storage and secretion of cellular lipids. J Lipid Res 
1991; 32: 1539-70. 
6. Ottey K, Wood LC, Elias PM et al. Cutaneous 
permeability barrier disntption increases fatty acids 
synthetic enzyme activity in the epidermis of hairless 
mice. J Invest Dermatol 1995; 104: 401-5. 
7. Ghadially R, Brown BE, Menon GK et al. The 
aged epidermal permeability barrier: structural, functional 
and lipid biochemical abnormalities in humans and a 
senescent murin model. J Ciin Invest 1994; 95: 
2281-90. 
8. Ghadially R, Brown BE, Hanley K et al. Decreased 
epidermal lipid synthesis accounts for altered barrier 
function in aged mice J Invest Dermatol 1996: 106: 
1064-69 
9. Hohl D. Comified celi envelope. Dermatologica 
1990; 180: 201-11 
10. Maestrini E, Monaco AP, Mcgrath JA et al. A 
molecular defect in loricrin, the major component of 
the cornified celi envelope, underlies Vohwinkel's 
syndrome. Nat genet 1996; 13: 70-7. 
11. Robinson N, Lapic S, Welter JF, Eckert RL. 
SlO0All, Sl00Al0, annexin 1, desmosomal proteins, 
srna!! proline-rich proteins,plasmogen activator inhibitor 
2 and involucrin are components of CE. J Biol Chem 
1997; 272: 12035-46 
8 
12. Hohl D, Huber M, Frenk E. Analysis of comified 
cel! envelope in lamellar ichthyosis. Arch Dermatol 
1993; 129: 618-24. 
13. Parmantier L, Blanchet-Bardon C, Nguyen C et 
al. Autosomal recessive lamellar ichthyosis: identification 
oj a new mutation in TGM-1 and evidence for 
genetic heterogeneity. Hum Mol Genet 1995; 4: 
1142-52. 
14. Huber M, Yee VC, Buni et al. Consequences of 
seven novel mutations on the expression and structure 
of keratinocyte transglutaminase. J Biol Chem 1997; 
272: 21018-26 
15. Elias P. Brown BE, Ziboh VA. The permeability 
barrier in essential fatty acid deficiency. Evidence for 
a direct role of linoleic acid in barrier function. J 
Invest Dermatol 1983; 74: 230-3 
16. Elias P, Cooper ER, Korc A, Brown BE. 
Percutaneous transport in relation to stratum comeum 
structure and lipid composition, idem 1981; 76: 297-
301 
17. Enders F. Dermatitis und Ekzemerkrankungen. 
Braun-Falco O, Plewig G, Wolf HH. Dermatologie 
und Venerologie, Springer, Berlin 1996, p. 407. 
18. Lavrijsen APM, Bouwstra JA, Gooris GS et al. 
Reduced skin barrier function parallels abnormal 
stratum comeum lipid organization in patients with 
lamellar ichthyosis. J lnvest Dermatol 1995; 105: 
619-24. 
19. Schafer L, Kragballe K Abnormalities in epidermal 
lipids in patients with atopic dermatitis. idem 1991; 
96: 10-15. 
20. Shapiro LI, Weiss R. Bu.xman MM et al. Enzymatic 
basis of typical x-linked ichthyosis. Lancet 1978; II: 
756-7. 
21. Williams ML, Elias PM. Increased cholesterol 
sulfate content of stratum comeum in recessive x-
linked ichthyosis. J Clin Invest 1981; 68: 1404-10. 
22. Nakamura T, Matsuzawa Y, Okano M et al. 
acta dermatovenerologica A.P.A. Vol 7, 98, No 1 
Stratum comeum barrier 
Characterization of low-density lipoproteins from patients 
with recessive X -linked ichthyosis. Atherosclerosis 1988, 
70: 43-52. 
23. Williams ML,Elias PM. Elevated n-alkanes in 
congenital ichthyosiform erythroderma. Phenotypic 
differentiation of two types of autosomal recessive 
ichthyosis. I Ciin Invest 1984; 74: 296-300. 
24. Dale BAK, Holbrook A, Fleckman P et al. 
Heterogeneity in harlequin ichthyosis, an inbom error 
of epidermal keratinization. : variable morphology and 
structural protein expression and a defect in lamel/ar 
granules. I Invest Dermatol 1990; 94: 6-18. 
25. Elias PM. Stratum comeum architecture, metabolic 
activity and interactivity with subjacent cell layers. 
Exp Dermatol 1996; 5: 191-201. 
AUTHORS' ADDRESSES 
Aleksej Kansky MD,PhD, Department of Dermatology, University Clinical Center, 
Zaloška 2, 1525 Ljubljana, Slovenia 
Julijana Kristl, PhD, professor of pharmacy, Faculty of Natura! Sciences, Dpt Pharmacy, Aškerčeva 7, 
1000 Ljubljana, Slovenija 
JO acta dermatovenerologica A.P.A. Vol 7, 98, No 1