Sebum and sebaceous glands

Definition and function

Sebaceous follicle

Sebaceous follicle, composed of a hair follicle and sebaceous gland which releases sebum through follicular canal onto the skin

What is sebum? Sebum is a viscous fluid, chemically complex oil, intrinsic product of the skin sebaceous glands, that eventually excreted onto the surface of the skin, seemingly lubricates the stratum corneum and coats hair. Sebum secretion is species specific, hormonally controlled, genetically influenced and limitation of supply of fatty acids precursors. Sebaceous glands, located in the dermis, open up in infundibulum of a hair follicle, give rise to the acid mantle with a pH in the range of 4.5-6 except for certain areas, known as physiological holes of the acid mantle, comprised of interdigital region, the axilla and anogenital area, where higher pH is maintained . The acid mantle works to combat pathogens, viruses, bacteria, which generally are of alkaline pH. Sebum functions in skin moisture retention, thermoregulation as well as sun protection. This barrier also imparts distinctive function in immunology and microbiology of the skin by regulating inflammatory markers and modulation of the skin microbiome.

A growing cognizance of sebaceous glands over the past decade, deeply constitutional to pathophysiology of the skin, delivers a broader and more integrated views of the function of the integument. Sebaceous glands’ sebum secretion is on a holocrine platform, built upon disintegration of sebocytes where their lipids synthesis occurs. These epithelial glands reside in the dermis, lined with sebocytes, equipped with hormonal receptors and embody skin’s androgen homeostasis, a virtue by which they are properly regarded as an endocrine organ. Sebaceous glands almost always are found associated with hair follicles where these glands secretions end up to with some exceptions such as meibomian glands in eyelids which, without intervention, deliver their content to the surface of the epithelium.

Sebum ought to be differentiated from skin surface lipids, and the two nomenclatures may not interchangeably be used since skin surface lipids are derived from two major sources, sebaceous glands which produces sebum and makes up to 90% of skin surface lipids, and epidermal keratinocytes. Distribution of sebaceous glands in different areas of the skin contribute to different composition of skin lipids in various areas. Rich areas of sebaceous glands such as forehead have a surface lipid composition very similar to sebum.

Its production varies with age with an onset at puberty and a nadir after menopause in women or after sixth decade in men. Sebaceous glands differentiation and proliferation is hormonally-controlled and androgen-dependent via binding to androgen nuclear receptors as all enzyme for androgen production and modulation are available in the skin, with 5alpha-dihydrotestosterone (DHT), the principal player. Men’s skin in general generates more secretions, which could be explained by higher level of androgens. Corticotropin releasing hormone, CRH, is another hormone found in the skin which regulates sebocytes’ function by tempering synthesis of IL-8 in these cells.

Sebum lipid content

Sebum composition, Glycerides, Free fatty acids (FFA), Wax esters (WE), Squalene (SQ), Cholesterol esters (CE), Cholesterol (CH)

Composition

Following differentiation and apoptosis of sebocytes, sebum is formed in sebaceous glands by decomposition of lipid-containing cells, sebocytes, so cell debris, disintegrated mature sebocytes, as well as matrix metaloproteinases can be found in its lipids. Three major lipid classes in human variant are triglycerides and free fatty acids, FFA (58%), wax esters, WE, (26%) and squalene , SQ(12%). Importantly, synthesis of SQ and WE is characteristic of sebaceous gland activity and is found no where else in the body even in epidermal surface lipids excreted from keratinocytes.  Moreover, branched chain fatty acids and lipids with specific pattern of unsaturation are also exclusive to the sebum. Highly specific and concentrated sebum, squalene is an unsaturated hydrocarbon and withal a precursor of cholesterol in most human tissues, where this conversion occurs. The triglycerides and FFA make up less than 60 percent of sebaceous glands products while their presence in skin surface lipids reaches to about 40 percent.

Free fatty acids

They form 15-30% and by some other reports 5-40% of sebaceous glands output. The two most abundant are sapienic acid (C16 : 1Δ6) and sebaleic acid (C18 : 2Δ5,8), found exclusively in the sebaceous secretions. Role of free fatty acids in comedone formation spawns controversy and various reports encourage cleaving to caution. Sapienic acid, which comprises 25% of total sebocyte-manufactured fatty acids, demonstrates inhibitory effect on staphylococcus aureus,  a suggested culprit in chronic inflammatory skin diseases including rosacea, psoriasis and in acne vulgaris via stimulation of toll like receptors 2 (TLR2), the most well described bacterial pathogen in acne is p. acnes.  Another study also supports antimicrobial activity of stratum corneum lipids against methicilin resistant staphylococcus aureus (MRSA), far greater effective than mupirocin. This product of sebocytes is not found in human diet as only a few plant species produces this fatty acid. In contrast, sebaleic acid, a polyunsaturated fatty acid formed in sebocytes by elongation of sapienic acid, is esteemed pro inflammatory and chemoattractant for neutrophils.

Squalene

Comprises about 12-20% of sebum, another study suggest 10-14%, squalene, a long unstaturated hydrocrabon chain, is exclusive to sebaceous gland activity and in other tissues converts to cholesterol. Despite its role in UV protection, SQ, amid highly unsaturated skin surface lipids, is more vulnerable to peroxidation and formation of squalene peroxide, proposed to be comedogenic and inductive of contact dermatitis. Peroxidation of squalene may also lead to an inflammatory response in keratinocytes by lipooxygenase activation and upregulation of IL-6 resulting in pilosebaceous duct hyperkeratinization.

Wax esters

The second most common lipid of sebaceous glands, wax esters make up to 30% of sebum content and their biosynthesis is a marker of sebogenesis and sebocyte function and differentiation. Esterification of sebum free fatty acids with fatty alcohols lead to formation of these skin oils, of paramount importance in skin barrier function. Overzealous sebaceous glands have been proposed to be depleted in linoleic acid content of their WE, whose synthesis in sebaceous glands is related to exclusive beta oxidation of linoleic acid.

Sebum branched chained fatty acids and lipids with unique unsaturation pattern

Branched chain fatty acids and lipids with specific unsaturation pattern. Sapienic acid (C16 : 1Δ6) and sebaleic acid (C18 : 2Δ5,8)

 

Sebum and sebaceous gland anatomy: SG: sebaceous gland, B: bulge region containing stem cells, HF: hair follicle, IFE: interfollicular epidermis

Sebaceous gland(SG) and hair follicle(HF) anatomy

Sebaceous glands anatomy and distribution

What is sebaceous follicle? Hair follicle along with adjacent sebaceous gland are called sebaceous follicle. Sebaceous gland is a cutaneous gland that secretes sebum by releasing it into a duct which carries it to hair follicle. The greatest concentration of sebaceous glands, and the largest glands, are on the face, nose, cheeks and chin, forehead and scalp. Palms and soles are the only areas of the body where sebaceous glands are not associated with hair follicles, which explains why sometimes sebaceous follicles and hair follicles are used interchangeably. Sebaceous glands are scarcely active in children.

Sebum changes in acne:

Squalene peroxide comedogenesis

Squalene peroxide comedogenesis. A) intact skin B) keratinocyte proliferation and increased inflammatory mediators in the dermis after exposure to squalene peroxide.

Sebum alterations during course of acne is one of the goals of any protocol aim to to alleviate this skin disease. Several lines of evidence support the concept that a high level of its secretion from sebaceous follicles is a contributing cause of oily skin and comedogenesis. On the other hand, change in sebaceous glands secretions  content imparts a culprit in pathogenesis of this chronic inflammatory skin disorder. Two pivotal mechanisms substantiate in comedogenesis due to change in composition of sebum in acne patients. First, alteration in ratio of saturated to unsaturated FA in sebum of due to triglyceride metabolism under influence of p. acnes, which is proinflammatory. Second, oxidative stress and lipid peroxidation especially formation of squalene peroxide from squalene by UV irradiation, has been found to be comedogenic by giving rise to proliferation of keratinocytes and releasing inflammatory markers.

The insight that sebaceous glands FA composition is not fixed and it varies with increased sebogenesis is proved by finding increased sebaleic acid and decreased linoleic acid in acne patients compare to normal controls. Depleted linolenic acid challenges epidermal barrier function and increases vulnerability of comedonal wall to inflammatory mediators and precipitates microcomedone formation. The change in sebum composition occurs in two axes, one involves lipid class composition, more WE than CE and the other implicates fatty acid proportions, more Δ6 compare with Δ9.  Gravely susceptible to low proportion of linoleate, a remodeling in skin ceramides occurs and follicular epithelium shifts from linoleate-rich acylceramides to sebaceous-fatty-acids acylcermides, which, in turn culminates in hyperkeratosis of follicular epithelium. Squalene increase is suggested as the primary lipid alteration due to sebogenesis in patients with acne and its enhanced ratio in the sebum amounts to severity of acne vulgaris, upregulated 2.2 folds.

Sebum and dry skin

Several studies in the past thirty years propose that skin in maintaining its barrier to water loss is not dependent to sebum as children with almost zero sebum secretion do not generally show dry skin. Another study in elderly was found no association between dry skin and sebaceous glands activity. Expressing nuclear hormone receptors, sebaceous glands PPAR, peroxisome proliferator-activated receptor, engage in lipid metabolism and inflammation. Amid PPAR isoforms, PPAR-γ s signifies an instrumental role in sebaceous lipid synthesis induced by oxidative stress, de-escalation of inflammatory mediators and sebocytes proliferation. Drugs which target these nuclear hormone receptors are proposed to be beneficial in treatment of these skin disorders.

Enlargement of sebaceous glands has been introduced to be associated with skin aging, in a benign condition known as sebaceous hyperplasia and withal androgenic alopecia. Sebaceous hyperplasia presents itself with small, yellowish papules most commonly on the face, nose, forehead, cheeks are frequently involved, as well as on the body.

Principal factors in sebum regulation

Influencing factors in sebum synthesis

Factors which affect sebum

Androgen synthesis in sebocytes, a fulcrum of sebaceous glands hemeostasis, breeds a dialogue between the two and renders sebaceous glands an endocrine medium. In hormonally-mediated acne androgens heighten sebum output giving rise to oily skin, which explains role of hormone therapy in treatment of acne. Increase in secretion is almost always seen in individuals with acne and control of hypersecretion of skin lipids and its regulation undoubtedly implicates in treatment. Many drugs used for various froms of acne vulgaris, in one way or another affect dynamism of sebaceous gland. Propionibacterium acnes, the bacteria which has been remarked with a causal link to acne lesions, affects sebaceous glands lipogenesis and changes skin surface lipids composition by delivering less complex lipid structures, shifting from triglycerides to free fatty acids, as a by product of its metabolization. Propionibacterium acnes affects sebaceous lipogenesis, inflammation and innate immunity at piolosebaceous level. Some studies provide evidence on how polyphenols and procyanidines may mitigate increase in acid mantle secretion and challenge acne pathology. Another well known manipulator of relationship between its secretion and acne lesions is calcium and vitamin D3. Sebocytes vitamin D receptor has been verified by several lines of study. Indeed, an increase in extracellular calcium and decrease in 1,25(OH)2D3 may account for increase in sebaceous gland volume and lipogenesis.