review and ceramides, which are associated with the stratum corneum were significantly increased, possibly as a compensatory mech- anism to maintain barrier function in the context of sebocyte hypoplasia.11 While it is clear that SCD1 in the skin plays a critical role in maintaining sebaceous lipids, a potential role for SCD1 in regulating the water permeability of the epidermis is as yet unre- solved. Asebia J1 mice naturally lacking SCD1 have been shown to have no impairment in their skin permeability,2 despite sig- nificant sebocyte atrophy. However, asebia 2J mice, as well as an additional model of global SCD1 deletion have been reported to have increased skin permeability.10,17 The differences in pheno- types observed using two different models of SCD1 deficiency suggest that the loss of sebaceous lipids per se is not sufficient to induce a loss of the epidermal permeability barrier. It is pos- sible that secondary changes, including reduced surface free cho- lesterol, decreased ceramides or increased dermal inflammation mediate the changes in transepidermal water loss observed in some models of SCD1 deficiency.1,2,10,11,17,24,25 Stearoyl-CoA Desaturase 2 SCD2 shares significant sequence homology with SCD1 and is primarily expressed in the brain.12 Unlike SCD1 which is mainly expressed in the dermal layer of skin, SCD2 is expressed to a greater extent in the epidermis and plays an important role in maintaining an intact skin permeability barrier. Mice with a targeted deletion of SCD2 (Scd2-/- mice) have a 70–100% mor- tality rate within 24 hours of birth, primarily due to alterations in epidermal lipid content and composition.12 Scd2-/- mice have increased skin barrier permeability due to significant decreases in skin cholesterol esters, triglycerides, acylceramides and gluco- sylacylceramides. While lamellar bodies were present in normal numbers in skin of Scd2-/- mice, their internal contents were sub- stantially reduced, and lipid delivery to the stratum corneum was decreased.12 As anticipated, delta-9 monounsaturated fatty acids were significantly lower in skin lipids of Scd2-/- mice. In addition, linoleic acid, the main epidermal fatty acid in mice, was reduced by 80% in the acylceramide fraction and increased by 30% in the phospholipid fraction of skin lipids from these mice. This prefer- ential channeling of linoleic acid towards phospholipid synthesis may be a compensatory mechanism to maintain membrane flu- idity in the absence of monounsaturated fatty acids. In addition to changes in lipid content and composition, keratinocyte differ- entiation was also impaired in Scd2-/- mice. Interestingly, SCD1 expression was variably induced in Scd2-/- mice, and the degree of induction of SCD1 appeared to determine the chance of survival of Scd2-/- mice into adulthood.12 These findings underscore the importance of in situ delta-9 desaturation in maintaining skin barrier function. review Stearoyl-CoA Desaturase 3 The Scd3 gene shares 91 and 88% sequence homology in the pro- tein coding sequence with Scd1 and Scd2, respectively. SCD3 dis- plays specificity towards palmitoyl-CoA as a substrate.13,26 SCD3 expression is limited to the Harderian gland and skin of the mouse, and it is expressed at significantly lower levels than SCD1 in the skin. In the skin, SCD3 expression is limited to the seba- ceous gland, but it is only expressed in differentiated sebocytes, unlike SCD1, which is expressed in the undifferentiated cells at the base of the sebaceous gland.13 Like Scd1, the Scd3 gene is also regulated throughout the hair cycle and is expressed at signifi- cantly greater levels in the skin of male rather than female mice.13 While SCD1 is not required for SCD3 expression, SCD3 expres- sion is dramatically reduced in skin of Scd1-/- mice due to the loss of sebocyte differentiation in mice lacking SCD1. However, an independent role for SCD3 in maintaining skin function has not yet been described. Delta-6 Desaturase The delta-6 desaturase FADS2 has been ascribed a role in modu- lating skin lipid composition.14,15,27 FADS2, which is expressed in multiple tissues including liver, brain and skin, is known to catalyze desaturation of at least five distinct substrates including linoleate, linolenate and palmitate.28,29 In the sebaceous gland, FADS2 primarily desaturates palmitate to sapienate (16:1n-10), the most abundant fatty acid in human sebum.15 Consistently, a delta-6 desaturase deficiency has been clinically described to be accompanied by skin abnormalities.27 Similarly, mice with a targeted deletion of FADS2 exhibit cutaneoous abnormalities, including dermatitis.14 However, both in the described clinical case as well as in Fads2-/- mice, dietary supplementation with arachidonic acid ameliorates the cutaneous phenotypes, at least partially.14,27 This is in marked contrast to the models of delta-9 desaturase deficiency, i.e., Scd1-/- and Scd2-/- mice, which show no improvement of alopecia or skin lipid abnormalities despite supplementation of the diet with exogenous monounsaturated fatty acids. Conclusion It has become increasingly clear that the lipid composition of the skin is influenced by both sebaceous secretions from the dermal layer as well as enzymes expressed in the epidermis. Desaturases expressed in the various layers of skin exert a profound influence on lipid metabolism in the epidermis and overall lipid composi- tion of the skin. Studies in rodent models suggest that the main- tenance of skin lipid content and composition is important to the barrier function of the skin in regulating water and temperature balance in the skin as well as whole body energy homeostasis. References 1. Elias PM, Feingold KR. Lipids and the epidermal water barrier: metabolism, regulation and pathophysiology. Semin Dermatol 1992; 11:176-82. 2. Fluhr JW, Mao-Qiang M, Brown BE, Wertz PW, 4. Feingold KR. Thematic review series: skin lipids. The Crumrine D, Sundberg JP, et al. Glycerol regulates stra- role of epidermal lipids in cutaneous permeability bar- tum corneum hydration in sebaceous gland deficient rier homeostasis. J Lipid Res 2007; 48:2531-46. (asebia) mice. J Invest Dermatol 2003; 120:728-37. 5. Feingold KR, Man MQ, Menon GK, Cho SS, Brown 3. Feingold KR. The outer frontier: the importance of lipid BE, Elias PM. Cholesterol synthesis is required for metabolism in the skin. J Lipid Res 2009; 50:417-22. cutaneous barrier function in mice. J Clin Invest 1990; 86:1738-45. www.landesbioscience.com Dermato-endocrinology 63