The outermost cells, basal cell layer membrane, are small, nucleated, and devoid of lipid droplets.

This layer contains the dividing cells that replenish the gland as cells are lost in the process of lipid ex cretion. As cells are displaced into the center of the gland, they begin to produce lipid, which accumulates in droplets. Eventually the cells become greatly distended with lipid droplets, and the nuclei and other sub-cellular structures disappear. As the cells approach the sebaceous duct, they disintegrate and release their contents. Only neutral lipids reach the skin surface. Proteins, nucleic acids, and the membrane phospholipids are digested and apparently recycled during the disintegration of the cells.

Lipid Composition of Sebum

Human sebum, as it leaves the sebaceous gland, contains squalene, cholesterol, cholesterol esters, wax esters, and

Cholesterol ester
Wax ester
11

Triglyceride triglycerides (Fig. 77-3). During passage of sebum through the hair canal, bacterial enzymes hydrolyze some of the triglycerides, so that the lipid mixture reaching the skin surface contains free fatty acids and small proportions of monoglycerides and diglycerides in addition to the original components. The wax esters and squalene distinguish sebum from the lipids of human internal organs, which contain no wax esters and little squalene. Human sebaceous glands, however, appear to be unable to cyclize squalene to sterols such as cholesterol. The patterns of unsaturation of the fatty acids in the triglycerides, wax esters, and cholesterol esters also distinguish human sebum from the lipids of other organs. The "normal" mammalian pathway of desaturation involves inserting a double bond between the ninth and tenth carbons of stearic acid (18:0) to form oleic acid (18:1A9). However, in human sebaceous glands, the predominant pattern is the insertion of a A6 double bond into palmitic acid (16:0). The resulting sapienic acid (16:146) (see Fig. 77-3) is the major fatty acid of adult human sebum. Elongation of the chain by two carbons and insertion of another double bond gives sebaleic acid (18:2A5,8) (see Fig. 77-3), a fatty acid thought to be unique to human sebum.9
HO

Cholesterol A FIGURE 77-3 Human sebaceous gland lipids. The structures of the cholesterol ester, wax ester, and triglyceride are representative of the many species that are present. Two sebaceous-type unsaturated fatty acid moieties are shown: sapienic acid (16:146) (in the wax ester structure) and sebaleic acid (18:245,8) (in the triglyceride structure). Anteiso branching is shown in the alcohol moiety of the wax ester, and iso branching is shown in the triglyceride.

Sebaceous fatty acids and alcohols are also distinguished by chain branching. Methyl branches can occur on the next to last (penultimate) carbon of a fatty acid chain (iso branching), on the third from the last (antepenultimate) carbon (anteiso branching), or on any even-numbered carbon (internal branching). Examples of these unusual unsaturated and branchedchain moieties are included in the lipid structures shown in Fig. 77-3.

Function of Sebum
The precise function of sebum in humans is unknown. It has been proposed that its sole role is to cause acne. 1 The suggestion has been made that sebum reduces water loss from the skin's surface and functions to keep skin soft and smooth, although evidence for these claims in humans is minimal; however, as demonstrated in the sebaceous gland-deficient mouse (Asebia) model, glycerol derived from triglyceride hydrolysis in sebum is critical for maintaining stratum comeum hydration. 11 Sebum has been shown to protect the skin from infection by bacteria and fungi, at least in part because it contains immunoglobulin A, which is secreted from most exocrine glands.12 Vitamin E delivery to the upper layers of the skin protects the skin and its surface lipids from oxidation. Thus, sebum flow to the surface of the skin may provide the transit mechanism necessary for vitamin E to function.13

FACTORS REGULATING SEBACEOUS GLAND SIZE AND SEBUM PRODUCTION

Sebum production is continuous and is not controlled by neural mechanisms. The exact mechanisms underlying the regulation of human sebum production have not been defined. Clearly, sebaceous glands are regulated by androgens and retinoids, but other factors, such as melanocortins, peroxisome proliferator-acti-

vated receptors (PPARs), and fibroblast growth factor receptors (FGFRs) have been postulated to play a role as well.

Androgens

It has long been recognized that sebaceous glands require androgenic stimulation to produce significant quantities of sebum. Individuals with a genetic deficiency of androgen receptors (complete androgen insensitivity) have no detectable sebum secretion and do not develop acne. 14 However, there is still a question as to which androgen is physi ologically significant. Although the most powerful androgens are testosterone and its end-organ reduction product dihydrotestosterone, levels of testosterone do not parallel the patterns of sebaceous gland activity. For example, testosterone levels are many-fold higher in males than in females, with no overlap between the sexes, whereas average rates of sebum secretion are only slightly higher in males than in females, with considerable overlap between the groups. Also, sebum secretion starts to increase in children during adrenarche, a developmental event that precedes puberty by approximately 2 years. The weak adrenal androgen dehydroepiandrosterone sulfate (DHEAS) might be a significant regulator of sebaceous gland activity through its conversion to testosterone and dihydrotestosterone in the sebaceous gland. Levels of DHEAS are high in newborns, are very low in 2to 4-year-old children, and start to rise when sebum secretion starts to increase. In adulthood, DHEAS levels show considerable individual variation but are only slightly higher in men than in women on the average. There is a decline in DHEAS levels in both sexes starting in early adulthood and continuing throughout life. This decline parallels the decline of sebum secretion. DHEAS is present in the blood in high concentration. The enzymes required to convert DHEAS to more potent androgens are present in sebaceous glands.15 These include 30-hydroxysteroid dehydrogenase, 170hydroxysteroid dehydrogenase, and 5a-reductase. Each of these enzymes exists in two or more isoforms that exhibit tissue-specific differences in their expression. The predominant isozymes in the sebaceous gland include type 13p-hydroxysteroid dehydrogenase, type 2 17p-hydroxysteroid dehydrogenase, and type 15ccreductase.

Retinoids
Isotretinoin (13-cis retinoic acid) is the most potent pharmacologic inhibitor of sebum secretion. Significant reductions in sebum production can be observed as early as 2 weeks after use.16 Histologically, sebaceous glands are markedly reduced in size, and individual sebocytes appear undifferentiated, lacking the characteristic cytoplasmic accumulation of sebaceous lipids. Isotretinoin does not interact with any of the known retinoid receptors. It may serve as a prodrug for the synthesis of all-trans retinoic acid or 9-cis retinoic acid, which do interact with retinoid re ceptors; however, it has greater sebosuppressive action than does all-trans or 9-cis retinoic acid. 17 The mechanism by which 13-cis retinoic acid lowers sebum secretion is unknown, but it inhibits the 3ahydroxysteroid activity of retinol dehydrogenase and leads to decreased androgen synthesis.18 In addition, isotretinoin triggers cell cycle arrest in human sebocytes and immortalized cell culture models of human sebocytes (SZ95 and SEB-1) and also induces apoptosis in SEB-1 sebocytes.19-21 Inhibition of androgen synthesis, cell cycle arrest, and apoptosis by 13-cis retinoic acid may explain the reduction of sebaceous gland size after treatment.

Mlelanocortins

Melanocortins include melanocyte-stimulating hormone and adrenocorticotropic hormone. In rodents, melanocortins increase sebum production. Transgenic mice deficient in the melanocortin-5 receptor have hypoplastic sebaceous glands and reduced sebum production. 22 The melanocortin-5 receptor has been identified in human sebaceous glands, where it may play a role in the modulation of sebum production. 23

Peroxisome ProliferatorActivated Receptors

PPARs are orphan nuclear receptors that are similar to retinoid receptors in many ways. Each of these receptors forms heterodimers with retinoid X receptors to regulate the transcription of genes involved in a variety of processes, including lipid metabolism and cellular proliferation and differentiation. PPAR-a, PPAR-8, and PPAR-y receptor sub-types have been detected in basal sebocytes. PPAR-y is also detected in differentiated sebocytes. In patients receiving fibrates (PPAR-oc ligands) for hyperlipidemia or thiazolidinediones (PPAR-y ligands) for diabetes, sebum secretion rates are increased. Rat preputial cells serve as a model for human sebocytes in the laboratory. 25 In rat preputial cells, agonists of the PPAR-y receptor, such as drugs of the thiazolidinedione class, increase lipid accumulation. 26

Fibroblast Growth Factor Receptors

FGFR1 and FGFR2 are expressed in the epidermis and skin appendages. Expression of FGFR3 and FGFR4 is localized to dermal vessels and microvessels and is notably absent in epidermis and appendages. 27 FGFR2 plays an important role during embryogenesis in skin formation. 28 Germline mutations in FGFR2 lead to Apert syndrome, which is commonly associated with acne. In addition, somatic mutations in the same gene can lead to localized acne, but how this receptor is involved in sebaceous gland development and how its mutation leads to acne is unknown. 29,30

CONCLUSION
The regulation of human sebum production is complex. Advances are being 1. Downie MMT, Guy R, Kealey T. Advances in sebaceous gland research: Potential new approaches to acne management. IntJ Cosmet Sci 26:291, 2004 4. Merrill B et al: Tcf3 and Lef1 regulate lineage differentiation of multipotent stem cells in skin. Genes Dev

15:1688, 2001

made in this area, which may lead to al ternative therapies for the reduction of sebum and improvement in acne.

5. 9. 15.

KEY REFERENCES The full reference list for all chapters is available at www.digm7.com.

16.

Allen M et al: Hedgehog signaling regulates sebaceous gland development. Am J Pathol 163:2173, 2003 Nicolaides N: Skin lipids: Their biochemical uniqueness. Science 186:19, 1974 Chen W, Thiboutot D, Zouboulis C: Cutaneous androgen metabolism: Basic research and clinical perspectives. J

Invest Dermatol 119:992, 2002 Stewart M et al: Effect of oral 13-cis retinoic acid at three dose levels on sustainable rates of sebum secretion and on acne. J Am Acad Dermatol 8:532,1983 24. Trivedi NR et al: Peroxisome proliferator-activated receptors increase human sebum production. J Invest Dermatol 126:2002, 2006