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Essential fatty acids and acne Donald T. Downing, Ph.D., Mary Ellen Stewart, Ph.D., Philip W. Wertz, Ph.D., and John S. Strauss, M.D. Iowa City, IA Acne is characterized by hyperkeratosis of the follicular epithelium, leading to horny impactions that may lie dormant as open or closed comedones or may cause inflammation of the follicle. Although persons with acne have consistently been observed to have elevated levels of sebum secretion, no mechanism relating sebum secretion rates to comedogenesis is known. Acne patients have also been shown to have low levels of linoleic acid in their skin surface lipids. To explain this observation, the hypothesis is advanced that the linoleate concentration in human sebum depends on the quantity of linoleic acid present in each sebaceous cell at the commencement of its differentiation and on the extent to which this initial charge is diluted by subsequent endogenous lipid synthesis in each sebaceous cell. A corollary hypothesis holds that low concentrations of !inoleate in sebum impose a state of essential fatty acid deficiency on the cells of the follicular epithelium and induce the characteristic response of hyperkeratosis. Both hypotheses could hold, without there being a systemic deficiency of linoleic acid, simply as the result of elevated lipogenesis in individual sebaceous cells. (J AM ACAD DERMATOL 14:221-225, 1986.) Acne has long been thought to be influenced by dietary factors, and several reports have implicated essential fatty acid deficiency. 1-3 However, no firm support for this view has developed, and no successful treatment based on this idea has appeared. Nevertheless, our studies have provided evidence for a role of linoleic acid deficiency in acne, and we present here a hypothesis that may explain how a deficiency localized in the hair follicle could arise without there being any dietary cause. The hypothesis is based on recent developments concerning the physiology and biochemistry of sebaceous gland function and the pathogenesis of acne, as well as on recent data from our studies of sebum From the Marshall Dennatology Research Laboratories, The University of Iowa College of Medicine. Supported in part by Grants Nos. AM22083 and AM32374 from the U.S. Public Health Service. Accepted for publication Sept. 30, 1985. Reprint requests to: Dr. Donald T. Downing, 270 Medlabs, University of Iowa College of Medicine, Iowa City, IA/319-353-5788. composition and excretion and the role of linoleic acid in the structure and function of the epidermis. BACKGROUND Physiology and biochemistry of sebum secretion Sebum is synthesized in differentiating cells that are generated on the periphery of the sebaceous gland and move centripetally as they become engorged with lipid. Eventually, all of the subcellular organelles are degraded and the cells disrupt, allowing their lipid contents to pass through the sebaceous duct into the pilosebaceous canal. In humans the overall process from cell division to final rupture requires about 14 days.4 During this time the cells increase up to 150-fold in volume, almost all of which is occupied by lipid. Obviously an external carbon source is necessary to provide the material for this exuberant generation of lipid, but the circulating substrate is yet to be identified. Nevertheless, it is quite clear from analyses of sebum from various species that circulating lipids 221 222 J oumal of the American Academy of Dermatology Downing et at are not incorporated by the differentiated sebaceous cell. 5 Human sebum consists principally of triglycerides (57%), wax esters (26%), and squalene (12%), with small proportions of cholesterol and cholesteryl esters. Many of the component fatty acids are branched chain compounds, and more than half are monounsaturated with unusual double-bond positions not found in circulating lipids. Thus the fatty acid composition of the wax esters, as well as of the triglycerides, is such that most of the acids could not have been acquired from circulating lipids. Copious amounts of phospholipids are required to provide the cellular and subcellular membranes of the expanding sebaceous cells during their differentiation, and labeling experiments indicate that these lipids, too, are produced within the cell. 6 This is supported by the observation that the phospholipids contain fatty acids that are characteristic of the sebum of the species. 7,8 In the final stages of differentiation, when the membranes are degraded, the phospholipids also disappear, and it is presumed that their fatty acids become esterified with whatever hydroxylic lipids are available. These mechanisms explain why sebum does not contain phospholipids, in spite of the holocrine character of sebaceous gland function. Pathogenesis and clinical course of acne The first pathologic change in acne appears to be the formation of the comedo by a hyperkeratotic reaction of the follicular epithelium. 9 In such impacted follicles, large increases in the population of Propionibacterium acnes can subsequently occur. This organism is thought to be responsible for most of the hydrolysis of sebaceous triglycerides to free fatty acids and glycerol. Inflammatory acne may require rupture of the wall of the follicle and release of the contents into the dermis, where typical foreign-body reactions and chemotactic responses are elicited. In addition, permeation of chemotactic molecules through intact follicular epithelium may be involved in producing inflammation. Usually only a few lesions are inflamed at one time, although comedones may lie dormant and persist for years. Inflammatory acne usually occurs only after the large increase in sebum secretion rate that takes place at puberty, and it has been shown that all subjects with pustular acne have a high rate of sebum secretion. 1O Further support for the role of high sebum secretion rates in the pathogenesis of inflammatory acne is the accepted view that any treatment that reduces sebum secretion rate can alleviate the disease. This is true of treatment with estrogens I I or antiandrogens,12 with the prostaglandin synthetase inhibitor 5,8,1l,14-eicosatetraynoic acid, 13 or with the synthetic retinoid 13cis-retinoic acid. 14 •1s Nevertheless, it is clear that formation of uninflamed comedones often begins in the early stages of puberty, when sebum secretion rate is just beginning to rise. Role of linoleic acid in skin It has long been recognized that a dietary deficiency of linoleic acid can result in scaly skin and decreased epidermal barrier function. 16 With the discovery of the prostaglandins and related eicosanoid metabolites of linoleic acid, it seemed that the basis for essential fatty acid requirement had been determined. However, it has been demonstrated that linoleic acid itself can alleviate some of the cutaneous symptoms of essential fatty acid deficiency, even when its conversion to arachidonic acid, and subsequently to the eicosanoids, is prevented. 17,18 Reasons for the specific requirement of linoleic acid became clearer following elucidation of the structures of two series of linoleaterich epidermal lipids that appear to playa role in the formation of the water barrier. 19.20 These series are based on w-hydroxy acids with very long chains (C30 to C34). One series, the acylglucosyl ceramides, is thought to induce assembly of the lamellar granules in the epidermal granular cells. Removal of the glucose moieties produces the second series, the acyl ceramides. This process is accompanied by dispersal of the stacks of lamellar disks that are extruded from the granular cells, allowing their rearrangement into the multiple intercellular lipid bilayers that constitute the barrier. Relation between sebum secretion rate and linoleate content of sebum The first clear evidence of a connection between linoleate and acne was reported in 1976, when it was shown that patients with acne had a signifi- Volume 14 Number 2, Part 1 February, 1986 cantly lower level of linoleic acid in their skin surface lipids than nonnal,21 Subsequent studies have suggested that this effect results from the higher sebum secretion rates that are characteristic of acne, since there is an inverse relationship between secretion rate and the linoleate content of skin surface wax esters, 22 which are purely of sebaceous origin. Studies have now shown that reduction in the rate of sebum secretion by treatment with the antiandrogen cyproterone acetate 23 or with 13-cis-retinoic acid (unpublished data) causes a corresponding increase in the linoleic acid content of the sebaceous wax esters, as well as in the triglycerides, free fatty acids, and cholesteryl esters in the skin surface lipids. We now wish to present a hypothesis that has been formulated to explain these changes in linoleate content that result from changes in sebum secretion rate. A corollary addresses the question of how a low sebum linoleate concentration could initiate the development of acne. THE HYPOTHESIS The linoleate concentration in human sebum depends on the quantity of linoleic acid present in each sebaceous cell at the commencement of its differentiation and on the extent to which this initial endowment is diluted by the subsequent endogenous synthesis of lipid in each sebaceous cell. At the time of cell division, when the sebaceous cells still have contact with the basement membrane, they still have access to circulating lipids, including linoleate. However, studies of sebum composition indicate that once sebum synthesis begins, no further lipids are accepted from the circulation, so that the more sebum that is synthesized per cell, the more the initiallinoleate content will be diluted. Most likely, the linoleate initially will be incorporated into phospholipids in the cell membranes. This linoleate will be released and incorporated into each of the sebaceous ester lipids at the time of final cell disruption, in proportion to the relative rates at which these lipids are being synthesized at the time of cell disintegration. Cholesteryl esters should incorporate the greatest proportion of this linoleate, since they are likely to be synthesized principally at the end of the life of the cells. Triglyceride should also in- Essential fatty acids and acne 223 corporate much of the linoleate, since diglyceride intermediates already containing linoleate should become available through hydrolysis of the phospholipids. However, triglycerides are synthesized throughout the differentiation of the sebaceous cell, under conditions in which little linoleate may be available. Wax esters also are known to be synthesized continuously during the differentiation of the sebaceous cells, and hence only a small proportion would be synthesized at the time of cell disruption. The result of this scenario could be that the highest content of linoleate is found in the cholesteryl esters, the next highest in the triglycerides, and the lowest in the wax esters, which, in fact, is the case. 23 THE COROLLARY Low concentrations of linoleate in sebum impose a state of essential fatty acid deficiency on the cells of the follicular epithelium, thereby inducing the characteristic responses of hyperkeratosis and decreased barrier function. Like all epidermal cells, those of the follicular epithelium can be expected to obtain adequate essential fatty acids from the general circulation (albeit by diffusion from the dermis, since the epidermis lacks a vascular circulation). Additional fatty acids would be available from sebaceous lipids that diffuse in from the follicular lumen. However, when the secretion rate of sebum is high and, as a result, its linoleate concentration is low, the cells of the follicular epithelium might thereby be subjected to lipids deficient in essential fatty acids. This deficiency might be especially effective in influencing the cells if the linoleate-deficient lipids were presented as free fatty acids, which occurs when the sebaceous triglycerides are hydrolyzed by follicular bacteria (P. acnes and Malassezia furjur).24 Support for the corollary has been obtained by examination of the polar lipids recovered from comedones,25 the acyl ceramides of which contained only 6% linoleate among the esterified fatty acids, in comparison with 45% in the acyl ceramides from normal human epidermis. In comparison, epidermal acyl ceramides from essential fatty acid-deficient rats contained 2% esterified linoleate, whereas those from normal rats con- 224 Journal of the American Academy of Dermatology Downing et al tained 38%.26 These data can be taken as a clear indication of essential fatty acid deficiency in the comedo-fonning epithelial cells in which the acyl ceramides were synthesized. Furthennore, the esterified acids from the comedo acyl ceramides included a high proportion of L\6-hexadecenoic acid, which is available only from sebum, providing direct evidence that the cells of the follicular epithelium incorporate sebaceous fatty acids. This evidence of essential fatty acid deficiency in the follicular epithelium suggests three additional mechanisms that may be relevant to the pathogenesis of acne. First, as long as the barrier properties of the follicular epithelium are intact, availability of water is likely to be a limiting factor in the growth of follicular microorganisms. Decline in the effectiveness of the water barrier, which is characteristic of essential fatty acid deficiency, would therefore be likely to promote bacterial growth and the liberation of additional free fatty acids from sebaceous triglycerides. Second, penetration of the linoleate-deficient free fatty acids from the follicular lumen into the viable cells of the follicular epithelium would also be promoted by decreased barrier function, which would further compromise the ability of the epithelial cells to produce the !inoleate-rich lipids that are thought to be required for barrier function. Third, chemotactic factors would more readily penetrate the deficient follicular epithelium and promote inflammation. IMPLICATIONS The hypothesis indicates how elevated sebum production alone could result in essential fatty acid-deficient sebum, and the corollary postulates how this effect may result in the follicular hyperkeratinization that leads to acne. Together the hypothesis and the corollary may explain the effectiveness of treatments for acne that reduce sebum secretion (estrogens, antiandrogens , and 13-cisretinoic acid). However, it is clear that a change in sebum secretion rate can result either from a change in the amount of sebum synthesized per cell or from a change in the sebocyte mitotic rate (and thereby the number of sebocytes producing sebum). According to our present hypothesis, it is only an increase in the amount of sebum per cell that will reduce the linoleate content of sebum. Awakening of the pubescent sebaceous gland, under the influence of extragonadal honnones, appears to result in such an increase in the amount of sebum produced per sebocyte, since linoleate content decreases dramatically long before the principal increase in sebum secretion that ensues from the effects of testicular or ovarian testosterone. Thus our data on the decline in sebum linoleate concentration between 6 and 10 years of age correspond with the onset of comedonal acne in this age range. For the corollary to be valid, it must be the reduced concentration of linoleate, rather than a reduced amount, that results in deficiency of essential fatty acids, since the hypothesis predicts no change in the absolute amount of linoleate secreted by the sebaceous glands when its concentration is diluted by increased sebum output. The question is dependent on the specificity of the enzyme that incorporates the linoleate into the acyl ceramides. Ifthe specificity for linoleate were absolute, dilution of the available linoleate might not be significant, as long as the required absolute amount remained available. However, it is known that the specificity is not absolute, since in deficiency of essential fatty acids, oleate can replace linoleate. Furthermore, in comedones, L\6-hexadecenoic acid is also incorporated into the acyl ceramides. Therefore dilution of the available linoleate with sebaceous fatty acids affects the acyl ceramide composition and thereby disturbs the differentiation of the follicular epithelium. This circumstance leaves open the possibility that increased systemic availability of linoleate might help to counteract the effect of decreased linoleate concentration in sebum. REFERENCES 1. Michaelsson G: Diet and acne. Nutr Rev 39:104-106, 1981. 2. Hubler WR: Unsaturated fatty acids in acne. Arch Dermatol 79:644-646, 1959. 3. Hoehn GH: Acne and diet. Cutis 2:389-394, 1966. 4. Downing DT, Strauss JS: On the mechanism of sebum secretion. Arch Dermatol Res 272:343-349, 1982. 5. Downing DT: Mammalian waxes, in Kolattukudy PE, editor: Chemistry and biochemistry of natural waxes. New York, 1976, Elsevier Science Publishing Co., Inc., pp. 17-48. Volume 14 Number 2, Part 1 February, 1986 Essential fatty acids and acne 6. Downing DT, Strauss JS, Norton LA, et al: The time course of lipid formation in human sebaceous glands. J Invest Dermatol 69:407-412, 1977. 7. Stewart ME, Downing DT, Pochi PE, Strauss JS: The fatty acids of human sebaceous gland phosphatidylcholine. Biochim Biophys Acta 529:380-386, 1978. 8. Colton SW VI, Downing DT: The time course of lipid biosynthesis in horse skin, Biochim Biophys Acta 836:306-311, 1985. 9. Lavker RM, Leyden JJ, McGinley KJ: The relationship between bacteria and the abnormal follicular keratinization in acne vulgaris. J Invest Dermatol 77:325-330, 1981. 10. Harris HH, Downing DT, Stewart ME, Strauss JS: Sustainable rates of sebum secretion in acne patients and matched normal control subjects. JAM ACAo DERMATOL 8:200-203, 1983. 11. Pochi PE, Strauss JS: Sebaceous gland suppression with estradiol and diethylstilbesterol. Arch Dermatoll08:21O215, 1973. 12. Hammerstein J, Meckies J, Leo-Rossberg I, et al: Use of cyproterone acetate (CPA) in the treatment of acne, hirsutism and virilism. J Steroid Biochem 6:827-836, 1975. 13. Strauss JS, Pochi PE, Whitman EN: Suppression of sebaceous gland activity with eicosa-5 :8 : 11 : 14-tetraynoic acid. J Invest Dermatol 48:492-493, 1967. 14. Peck GL, Thomas TO, Yoder FW, et al: Prolonged remissions of cystic and conglobate acne with 13-cis-retinoic acid. N Engl J Med 300:329-333, 1979. 15. Farrell LN, Strauss JS, Stranieri AM: The treatment of severe cystic acne with 13-cis-retinoic acid: Evaluation of sebum production and the clinical response in a multiple-dose trial. JAM ACAo DERMATOL2:602-611 , 1980. 16. Holman RT: Essential fatty acid deficiency, in Holman RT, editor: Progress in the chemistry of fats and other 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 225 lipids. New York, 1968, Pergamon Press, Inc., pp. 275348. Prottey C: Investigation of functions of essential fatty acids in the skin. Br J DermatoI97:29-38, 1977. MacDonald ML, Rogers QR, Morris JG: Role oflinoleate as an essential fatty acid for the cat independent of arachidonate synthesis. J Nutr 113:1422-1433, 1983, Wertz PW, Downing DT: Olycolipids in mammalian epidermis: Structure and function in the water barrier. Science 217:1261-1262, 1982. Abraham W, Wertz PW, Downing DT: Linoleate-rich acylglucosylceramides of pig epidermis: Structure determination by proton magnetic resonance. J Lipid Res 26:761·765,1985. Morello AM, Downing DT, Strauss JS: Octadecadienoic acids in the skin surface lipids of acne patients and normal subjects. J Invest Dermatol 66:319-323, 1976. Stewart ME, Wertz PW, Grahek MO, Downing DT: Relationship between sebum secretion rates and the concentration of linoleate in sebum and epidermal lipids. Clin Res 33:684, 1985. (Abst.) Stewart ME, Greenwood R, Cunliffe WJ, et al: Effect of cyproterone acetate-ethinyl estradiol treatment on the percentages of linoleic and sebaleic acids in various skin surface lipid classes. Arch Dermatol Res. (Submitted for publication. ) Marples RR, Downing DT, Kligman AM: Influence of Pityrosporum species in the generation of free fatty acids in human surface lipids. J Invest Dermatol 58: 155-159, 1972. Wertz PW, Miethke MC, Long SA, et al: The composition of the ceramides from human stratum corneum and from comedones. J Invest Dermatol 84:410-412, 1985. Wertz PW, Cho ES, Downing DT: Effect of essential fatty acid deficiency on the epidermal sphingoFpids of the rat. Biochim Biophys Acta 753:350-355, 1983. ABSTRACTS Immunofluorescence in skin specimens from three . different biopsy sites in patients with scleroderma Chen ZY, Dobson RL, Ainsworth SK, et al: Clin Exp Rheumatol 3:11-16, 1985 Biopsies from nail fold, forearm, and buttock were compared with normal skin, sclerodermatous skin, and skin from patients with systemic lupus erythematosus. Nail fold skin was most reactive in eighteen scleroderma patients. The site for biopsy affects the chance of diagnostic findings. Normal skin was studied and was not reactive. P. C. Anderson, M.D. Depth of invasion and tumor thickness in primary cutaneous malignant melanoma. A study of 2012 cases Sondergaard K: Acta Pathol Microbiol Immunol Scand [AJ 93:49-55, 1985 This study of 2,012 patients with melanoma urges tne use of Clark levels. Melanomas from 0.76 to 1.5 mm thick, at each specific thickness had the poorer prognosis according to the depth of invasion by Clark's system. P. C. Anderson, M.D,