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Lipids in Skin Barrier Function

Andrea TH Lam, DVM
Veterinary Skin & Allergy Specialists
Veterinary Referral Center of Colorado
3550 South Jason St.
Englewood, CO 80110

Introduction:

Skin is a remarkable organ in which its primary function is to form a barrier between a living organism and its external environ-
ment. Protection against physical and chemical insults as well as the penetration of allergens and microbes is provided by this barrier.
The epidermis also plays a key regulatory role in the transcutaneous movement of water and solutes, essential for homeostasis. The
stratum corneum (SC), or uppermost layer of the epidermis, is likened to a “brick and mortar” model in which the corneocytes,
flattened, anucleate cells, act as “bricks”.
Corneocytes derive their strength and mechanical resistance through the formation of a cornified cell envelope, a rigid structure built
upon the cross-linkage of filaggrin, a filament-associated protein, with keratin fibers.1,2,3 These corneocytes are embedded in a rich,
non-polar lipid matrix or “mortar” which constitutes the permeability barrier.

Corneocyte Lipid Matrix

spinosum granulosum corneum
Stratum

TEM Processing
Stratum
Stratum Stratum
basale

Diagram of the Epidermis

Lipids:

The precursors of the SC intercellular lipids are formed in the upper spinous and granular layers of the epidermis. Lamellar
granules are prominent in the granular layer and contain stacks of lipid lamellae composed of lipid precursors such as phospholip-
ids, free sterols and glucosylceramides as well as β-defensin.4,5,6 As cells in the stratum granulosum differentiate, lamellar granules
fuse to the plasma membrane and extrude their contents into the intercellular spaces through exocytosis.1,2,3 Hydrolysis of sphingo-
lipids and phospholipids generate ceramides and free fatty acids respectively. The major lipids found in the SC interstices include
ceramides, free fatty acids, and cholesterol.1,3,5,7
Ceramides are a complex group of sphingolipids which contain a sphingoid base (such as sphingosine, phytosphingosine, or
6-hydroxysphingosine) linked to a variety of fatty acids.8,9 They are the most common SC lipid constituent, accounting for 30 to
50% of SC lipids.1,3,10 At least nine different classes of ceramides have been described to occur in human SC. Ceramides A and
B are covalently bound to cornified envelope proteins and aid in cellular adhesion. This, plus the tight, lateral packing formation
of these ceramides achieve limited permeability of the SC. 2,11,12,13 Other functions of ceramides include regulation of epidermal
growth factors and keratinocyte differentiation.14
Free fatty acids in the SC are synthesized within the epidermis rather than derived from dietary sources.14 They are responsible
for creating an acidic environment at the surface of the SC. 14,15,16 The role of cholesterol in the SC has not been entirely
elucidated; however, it is thought to act as a stabilizer of SC structure during temperature fluctuations.17,18 It is the combination
of all three of these lipid substrates that the integrity of the multi-lamellae lipid structure in the SC interstices is preserved.
 Skin Barrier Dysfunction in Dermatoses:

D isruption in skin barrier function can be caused by stripping of the naturally occurring lipids in the
SC by detergents, organic solvents and surfactants, or through genetic deficiencies. Impairment of
barrier function has been linked to both altered lipid composition and organization.10,19 It has been
well documented that ceramide deficiencies have been linked to increased transepidermal water loss
(TEWL) which in turn leads to a reduction in epidermal hydration. Xerosis and other barrier defects
can trigger immunological reactions that both perpetuate and sustain skin disease. This has been
described as the outside-inside hypothesis.20,21 Alternatively, inflammation of the epidermis caused
by allergens, irritants, chemical or physical trauma, autoimmune or neoplastic disease may trigger a
secondary barrier anomaly. This is known as the inside-outside hypothesis.20,21
In humans with atopic dermatitis, it is known that an innately impaired SC lipid barrier is present in
both lesional and non-lesional skin. Filaggrin mutations have been linked to increased TEWL and
decreased epidermal hydration and has been well documented in humans with atopic dermatitis.22,23,24
Changes in epidermal lipid levels are also believed to contribute to the pathogenesis of atopic dermati-
tis. It has been hypothesized that a decrease in the ceramide to cholesterol ratio may be partially TEM Processing
responsible for the functional aberrations in patients with atopic dermatitis.10,25
Dogs with atopic dermatitis have also been found to have an increase in TEWL in lesional26 and non-lesional skin.27 Ultrastructural
evaluation of skin from atopic dogs has shown that intercellular lipid lamellae are disorganized and markedly heterogenous when
compared to normal skin.28,29,30 There is a widening of intercellular spaces as well as abnormal release of lamellar bodies33 that is
exacerbated in lesional skin after specific allergen challenge.30
Various other dermatoses in humans, like ichthyosis and xerosis, have been traced to underlying lipid barrier dysfunction.

Treatment:

A side from addressing immunological factors that contribute to clinical signs, such as pruritus and inflammation, in diseases of
impaired skin barrier function, one might also consider the value of using topically applied materials to improve the appearance and
function of diseased skin. Many products in use today are moisturizers implying a water retaining property. However, many
moisturizing agents, such as urea, propylene glycol, and lactic acid not only function to hold water in the SC, but also promote
desquamation.14 Recent studies in topical therapeutics for the treatment of human atopic dermatitis have suggested that ceramide-
dominant targeted lipid-replacement therapy may be useful in not only ameliorating clinical signs, but also reducing usage of
concurrent treatments.32
Yet another approach would be to topically deliver lipid precursors to diseased skin in order to encourage ceramide synthesis either
directly or through delivery of substrates used in ceramide biosynthesis pathways (like phytophingosine). More research in this
area is still necessary.

Conclusion:

The lipids in skin barrier function are essential in maintaining homeostasis by aiding in structural integrity as well as regulation of
water permeation. Disruption of lipid synthesis will cause an increase in TEWL and an alteration in the ratios of ceramides, free
fatty acids and cholesterol. By targeting these specific changes, it may be possible to ameliorate the clinical signs associated with
these conditions.

References:
1. Elias PM. Stratum Corneum Defensive Functions: An Integrated View. J Invest Dermatol 2005;125:183-200.
2. Elias PM. Epidermal lipids, barrier function, and desquamation. J Invest Dermatol 1983;80:44-9.
3. Madison, KC. Barrier Function of the Skin: “La Raison d’Etre” of the Epidermis. J Invest Dermatol 2003;121:231-41.
4. Elias PM, Hatano Y, Williams ML. Basis for the barrier abnormality in atopic dermatitis: Outside-inside-outside pathogenic mechanisms. J Allergy Clin Immunol 2008;121:1337-43.
5. Aberg KM, Man MQ, Gallo RL et al. Co-regulation and interdependence of the mammalian epidermal permeability and antimicrobial barriers. J Invest Dermatol 2008;128:917-25.
6. Denda M, Sato, J, Tsuchiya T, Elias PM, Feingold KR. Low humidity stimulates epidermal DNA synthesis and amplifies the hyperproliferative response to barrier disruption: implication
for seasonal exacerbations of inflammatory dermatoses. J Invest Dermatol 1998;111:873-8.
7. Reiter LV, Torres SM, Wertz PW. Vet Dermatol 2009:20;260-266.
8. Wertz PW, Miethke MC, Long SA et al. The composition of the ceramides from human stratum corneum and from comedones. J Invest Dermatol 1985;84:410-2.
9. Robson KJ, Stewart ME, Michelsen S et al. 6-hydroxy-4-sphingenine in human epidermal ceramides. J Lipid Res 1999:35;2060-8.
10. Choi MJ, Maibach HI. Role of Ceramides in Barrier Function of Healthy and Diseased Skin. Am J Clin Dermatol 2005:6;215-23.
11. Fartasch M. The nature of the epidermal barrier: structural aspects. Adv Drug Deliv Rev 1996:18;273-82.
12. Kerscher M, Korting HC, Scharfer-Korting M. Skin ceramides: structure and function. Eur J Dermatol 1991:1;39-43.
13. Farin F, Lambers H, Keuning W et al. Human skin identical ceramides. Cosmet Toiletries 1995:3;126-32.
14. Coderch L, Lopez O, de la Maza A,Parra JL. Ceramides and Skin Function. Am J Clin Dermatol 2003:4;107-129.
15. Jungersted JM, Hellgren LI, Jemec GBE, Agner T. Lipids and skin barrier function - a clinical perspective. Contact Dermatitis 2008:58;255-62.
16. Schaefer H, RedelmeierTE. Skin barrier: principles of percutaneous absorption. Basel: Karger, 1996.
17. Velkova V, Lafleur M. Influence of the lipid composition on the organization of skin lipid model mixtures an infrared spectroscopy investigation. Chem Phys Lipids 2002:117;63-74.
18. Norlen I. Skin barrier structure and function: the single gel phase model. J Invest Dermatol 2001:117;830-6.
19. Schuerer NY, Elias PM. The biochemistry and function of stratum corneum lipids. Adv Lipid Res 1991;24:27-56.
20. Ghadially R, Reed JT, Elias PM. Stratum corneum structure and function correlates with phenotype in psoriasis. J Invest Dermatol 1996:107;558-64.21.Elias PM, Wood LC, Feingold KR.
Epidermal pathogenesis of inflammatory dermatoses. Am J Contact Dermatol 1999:10;119-26.
22. O’Regan GM, Irvine AD. The role of filaggrin loss-of-function mutations in atopic dermatitis. Curr Opin Allergy Clin Immunol 2008:8;406-10.
23. O’Regan GM, Sandilands A, Irwin McLeain WH, Irvine AD. Filaggrin in atopic dermatitis. J Allergy Clin Immunol 2008:112;689-93.
24. Cork MJ, Danby SG, Vasilopoulos Y, Hadgraft J et al. Epidermal Barrier Dysfunction in Atopic Dermatitis. J Invest Dermatol 2009:129;1892-908.
25. Di Nardo A, Wertz P, Giannetti A, Seidnari S. Ceramide and Cholesterol Composition of the Skin of Patients with Atopic Dermatitis. Acta Derm Venereol 1998:78;27-30.
26. Hightower K, Marsella R, Flynn-Lurie A. Effects of age and allergen exposure on transepidermal water loss in a house dust mite-sensitized beagle model of atopic dermatitis. Vet
Dermatol 2010:21;89-96.
27. Shimada K, Yoon J-S, Yoshihara T et al. Increased transepidermal water loss and decreased ceramide content in lesional and non-lesional skin of dogs with atopic dermatitis. Vet Dermatol
2009:20;541-6.
28. Inman AO, Olivry T, Dunston SM et al. Electron Microscopic Observations of Stratum Corneum Intercellular Lipids in Normal and Atopic Dogs. Vet Pathol 2001:38;720-3.
29. Piekutowska A, Pin D, Reme CA, Gatto H, Haftek M. Effects of a Topically Applied Preparation of Epidermal Lipids on the Stratum Corneum Barrier of Atopic Dogs. J Comp Path
2008:138;197-203.
30. Marsella R, Samuelson D, Doerr K. Transmission electron microscopy studies in an experimental model of canine atopic dermatitis. Vet Dermatol 2010:21;81-8.
31. Marsella R, Samuelson D. Unravelling the skin barrier: a new paradigm for atopic dermatitis and house dust mites. Vet Dermatol 2009:20;533-40.
32. Chamlin SL, Kao J, Frieden IJ, Shen MY et al. Ceramide-dominant barrier repair lipids alleviate childhood atopic dermatitis: Changes in barrier function provide a sensitive indicator of
disease activity. J Am Acad Dermatol 2002:47;198-208.