Epidermal Lipogenesis Research Articles

Cetacean epidermal specialization: A review.

Cetacean skin continues to be the investigative focus of researchers from several different scientific disciplines. Yet, most research on the basic functions of lipo-keratinocytes, which constitute most of the cetacean epidermis, providing the first layer of protection against various environmental aggressors (including an ever-increasing level of pollutants), is restricted to specialized literature on the permeability barrier only. In this review, we have attempted to bring together much of the recent research on the functional biology of cetacean skin, including special adaptations at the cellular, genetic and molecular level. We have correlated these data with the cetacean permeability barrier's unique structural and metabolic adaptations to fully aquatic life, including the development of secondary barriers to ward off challenges such as biofouling as well as exposure to extreme cold for the epidermis, which is outside of the insulation provided by blubber. An apparent contradiction exists between some of the reported gene loss for lipogenic enzymes in cetacean skin and the high degree of cetacean epidermal lipogenesis, as well as loss of desmocollin 1 and desmoplakin genes [while immunolocalization of these proteins is reported (Journal of Anatomy, 234, 201)] warrants a re-evaluation of the gene loss data.

UV-Induced Reduction of ACVR1C Decreases SREBP1 and ACC Expression by the Suppression of SMAD2 Phosphorylation in Normal Human Epidermal Keratinocytes.

Activin A receptor type 1C (ACVR1C), a type I transforming growth factor-β (TGF-β) receptor, has been implicated in sensitive skin and psoriasis and is involved in the regulation of metabolic homeostasis as well as cell proliferation and differentiation. In this study, we identified a novel role of ACVR1C in the ultraviolet (UV)-irradiation-induced reduction of epidermal lipogenesis in human skin. UV irradiation decreased ACVR1C expression and epidermal triglyceride (TG) synthesis in human skin in vivo and in primary normal human epidermal keratinocytes (NHEK) in vitro. Lipogenic genes, including genes encoding acetyl-CoA carboxylase (ACC) and sterol regulatory element binding protein-1 (SREBP1), were significantly downregulated in UV-irradiated NHEK. ACVR1C knockdown by shRNA resulted in greater decreases in SREBP1 and ACC in response to UV irradiation. Conversely, the overexpression of ACVR1C attenuated the UV-induced decreases in SREBP1 and ACC. Further mechanistic study revealed that SMAD2 phosphorylation mediated the ACVR1C-induced lipogenic gene modulation. Taken together, a decrease in ACVR1C may cause UV-induced reductions in SREBP1 and ACC as well as epidermal TG synthesis via the suppression of SMAD2 phosphorylation. ACVR1C may be a target for preventing or treating UV-induced disruptions in lipid metabolism and associated skin disorders.

Measuring the effects of topical moisturizers on changes in stratum corneum thickness, water gradients and hydrationin vivo

Moisturizers are the most commonly used topically applied product for the treatment of dry skin conditions. They affect many properties and functions of the stratum corneum but some moisturizers have been reported to be detrimental to barrier function. Stratum corneum barrier function is a composite of its total structure and thickness but few studies have taken this into account. As a biosensor, the stratum corneum (SC) will change its structure in response to treatment and a swelling effect has been clearly demonstrated by skin hydration. Recently several moisturizing agents have been shown to have an effect on SC swelling behaviour with conflicting results. However, there is a paucity of data reported for measuring the effects of long-term usage of moisturizers on SC thickness in vivo as, until recently, traditional techniques did not have the resolution to measure the effects of moisturizers on nonpalmoplantar body sites. The development of confocal Raman spectroscopy for use in human subjects provides noninvasive, real-time, in vivo measurement of SC water concentration profiles and we have also used this state of the art equipment to measure the effect of the long-term use of moisturizers on SC thickness for the first time. To validate the use of confocal Raman spectroscopy (CRS) to measure SC thickness and then use it to investigate the short- and long-term effects of moisturizers (one of which is known to improve SC barrier function) on SC thickness, water gradients and hydration. Two studies were conducted: (i) to validate the use of CRS for measuring SC thickness through comparison with optical coherence tomography (OCT); and (ii) once validated to use CRS to measure the long-term effects of three commercially available moisturizers (A, B, C) on SC thickness and water gradients, together with total hydration, over a 3-week period (2 weeks of treatment and 1 week regression) and compare the spectroscopy-derived hydration value with instrumentally derived capacitance hydration values. (i) A strong, positive correlation in SC thickness was obtained between CRS and OCT (OCT-derived thickness = 0.96 x CRS-derived thickness, r(2) = 0.93; P <0.0001). OCT was shown, however, to have a lower resolution than CRS in distinguishing SC thickness on thinner nonpalmoplantar body sites. Using the CRS method, differences in SC thickness were readily apparent on different body sites (cheek 12.8 +/- 0.9 microm, volar forearm 18.0 +/- 3.9 microm, leg 22.0 +/- 6.9 microm). (ii) Examining the effects of moisturizers in a blinded, randomized 3-week study in human volunteers (n = 14) demonstrated that only one commercially available formulation (A) changed SC water gradients, thickness and hydration as measured by CRS. These hydration data did not directly correlate with capacitance hydration values. (i) In vivo CRS was validated as a technique to measure SC thickness on both palmoplantar and, particularly, on nonpalmoplantar skin sites. (ii) Moisturizers improve skin moisturization but in this study only formulation A improved SC thickness, water gradients and hydration as measured by CRS. We hypothesize that this was due to compositional differences between the products. We believe that niacinamide (nicotinamide, vitamin B(3)) is probably contributing significantly to this effect, as it has been proven to increase epidermal lipogenesis and SC barrier function in other studies. These results show that by using CRS, we were able for the first time to determine the effect of moisturizer on multiple SC barrier endpoints including SC thickness, and water content as a function of depth and total SC water content.

Expression and regulation of 1-acyl-sn-glycerol- 3-phosphate acyltransferases in the epidermis

Phospholipids are a major class of lipids in epidermis, where they serve as a source of free fatty acids that are important for the maintenance of epidermal permeability barrier function. The phospholipid biosynthetic enzyme, 1-acyl-sn-glycerol-3-phosphate acyltransferase (AGPAT), catalyzes the acylation of lysophosphatidic acid to form phosphatidic acid, the major precursor of all glycerolipids. We identified an expression pattern of AGPAT isoforms that is unique to epidermis, with relatively high constitutive expression of mouse AGPAT (mAGPAT) 3, 4, and 5 but low constitutive expression of mAGPAT 1 and 2. Localization studies indicate that all five isoforms of AGPAT were expressed in all nucleated layers of epidermis. Furthermore, rat AGPAT 2 and 5 mRNAs increased in parallel with both an increase in enzyme activity and permeability barrier formation late in rat epidermal development. Moreover, after two methods of acute permeability barrier disruption, mAGPAT 1, 2, and 3 mRNA levels increased rapidly and were sustained for at least 24 h. In parallel with the increase in mRNA levels, an increase in AGPAT activity also occurred. Because upregulation of mAGPAT mRNAs after tape-stripping could be partially reversed by artificial barrier restoration by occlusion, these studies suggest that an increase in the expression of AGPATs is linked to barrier requirements.

Stratum corneum lipids: specificity, role, deficiencies and modulation

Lipids are important constituents of the human epidermis. Either free and organized into broad lipid bilayers in the intercorneocytes spaces, or covalently bound to the corneocyte envelope, they play a crucial role in permeability barrier function. This article presents the structures of various human skin ceramides, their role in the maintenance of skin barrier function and homeostasis, and their qualitative and quantitative changes in some cases of dry skin or atopic xerosis. Moreover, we show that reconstructed human skin models could provide valuable tools to assess in vitro the biological interest of active compounds on epidermal lipogenesis. Based on such in vitro studies, we assume that the association of vitamin C and some exogenous sphingolipid could enhance the endogenous ceramide content deficient in some cases of atopic dry skin.

Dropping lipids for epidermal defense.

Dropping lipids for epidermal defense.

Avian Epidermal Lipids: Functional Considerations and Relationship to Feathering

The avian epidermis is composed of unique sebokeratinocytes that elaborate and secrete sebum-like lipids as they cornify. In addition to the lipid droplets, the avian epidermis elaborates, but rarely secretes, lipid—enriched organelles, the multigranular bodies. The multigranular bodies are analogous to the lamellar bodies of mammals (Menon et al., 1991), the secretion of which results in formation of occlusive lipid bilayers characteristic of mammalian stratum corneum and providing the permeability barrier. However, in contrast to mammals, the avian multigranular bodies form the reserve barrier mechanism. In the basal state, when multigranular bodies are not secreted, the avian cutaneous barrier is deficient, but allows evaporative cooling for thermoregulation. However, under conditions of water deficit, multigranular body secretion allows for rapid facultative waterproofing, as shown in zebra finches (Taenyopygia guttata). In certain glabrous regions of the skin, such as the maxillary rictus, interdigital web, and combs and wattles in the domestic fowl, there is a high degree of epidermal lipid secretion. Also specialized feathers such as powder downs elaborate lipid rich material, which can be classified as secretion. Additionally, an inverse relation between epidermal lipogenesis and the degree of feathering has been demonstrated, as in temporarily bare areas (e.g., brood patches) and following permanent feather loss from the head accompanying attainment of maturity in certain ibises and storks. In the latter, the neo-apteria often hold large reserves of carotenoids dissolved in the lipid droplets, possibly related to an altered gradient of retinoids influencing feather morphogenesis. Unusual secondary functions of epidermal lipids include cosmetic coloration (e.g., in the Japanese Crested Ibis) and chemical defense (e.g., in the Pitohui).

Avian Epidermal Lipids: Functional Considerations and Relationship to Feathering1

The avian epidermis is composed of unique sebokeratinocytes that elaborate and secrete sebum-like lipids as they cornify. In addition to the lipid droplets, the avian epidermis elaborates, but rarely secretes, lipid—enriched organelles, the multigranular bodies. The multigranular bodies are analogous to the lamellar bodies of mammals (Menon et al., 1991), the secretion of which results in formation of occlusive lipid bilayers characteristic of mammalian stratum corneum and providing the permeability barrier. However, in contrast to mammals, the avian multigranular bodies form the reserve barrier mechanism. In the basal state, when multigranular bodies are not secreted, the avian cutaneous barrier is deficient, but allows evaporative cooling for thermoregulation. However, under conditions of water deficit, multigranular body secretion allows for rapid facultative waterproofing, as shown in zebra finches (Taenyopygia guttata). In certain glabrous regions of the skin, such as the maxillary rictus, interdigital web, and combs and wattles in the domestic fowl, there is a high degree of epidermal lipid secretion. Also specialized feathers such as powder downs elaborate lipid rich material, which can be classified as secretion. Additionally, an inverse relation between epidermal lipogenesis and the degree of feathering has been demonstrated, as in temporarily bare areas (e.g., brood patches) and following permanent feather loss from the head accompanying attainment of maturity in certain ibises and storks. In the latter, the neo-apteria often hold large reserves of carotenoids dissolved in the lipid droplets, possibly related to an altered gradient of retinoids influencing feather morphogenesis. Unusual secondary functions of epidermal lipids include cosmetic coloration (e.g., in the Japanese Crested Ibis) and chemical defense (e.g., in the Pitohui).

Incorporation of linoleic acid by cultured human keratinocytes

Linoleic acid is required for the formation and maintenance of the epidermal barrier, but most of the current in vitro keratinocyte culture systems are linoleic acid-deficient. The aim of the present study was to examine the efficiency of linoleic acid uptake in human keratinocyte cultures grown under submerged and air-exposed conditions in serum-free medium. The water-insoluble linoleic acid was bound to carrier molecules (cyclodextrin or bovine serum albumin). Comparable results were obtained with home-made and commercially available linoleic acid complexes. In the submerged cultures, the increase of the linoleic acid medium concentration (ranging from 0 to 20 microg/ml) resulted in a gradual increase in the linoleic acid cellular content, which exceeded 1.4 times the value found in native epidermis when the highest concentration of linoleic acid was used. The addition of linoleic acid did not alter the profile of the other epidermal fatty acids, with the exception of oleic acid, which decreased in parallel with the increasing linoleic acid content. While the content of linoleic acid found in phospholipids was similar to that in native epidermis, a large excess of linoleic acid was detected in triglycerides, the synthesis of which was markedly increased in cultures grown submerged in medium containing higher concentrations of linoleic acid. Under air-exposed conditions, the dermal substrate used seemed to be the most limiting factor for efficient linoleic acid supplementation. A low linoleic acid cellular content was detected when an inert filter was used. De-epidermized dermis was found to be the most permeable substrate for linoleic acid complexes. The cellular linoleic acid content increased in a parallel with the increasing linoleic acid concentration (ranging from 4 to 30 microg/ml), but the overall amount incorporated was lower than that in submerged cultures. The content of linoleic acid in the phospholipid and ceramide fractions isolated from reconstructed epidermis grown under air-exposed conditions was close to that of native epidermis, but the triglycerides remained abnormally enriched in linoleic acid, indicating persistence of some anomalies in epidermal lipogenesis in vitro.

The effect of topical coptidis rhizoma, corticosteroid and PUVA therapy on the epidermal lipogenesis of psoriasis

The effect of topical coptidis rhizoma, corticosteroid and PUVA therapy on the epidermal lipogenesis of psoriasis

Transepidermal water loss: the signal for recovery of barrier structure and function.

Previous studies have demonstrated that perturbations in barrier function stimulate epidermal lipid synthesis and that this increase can be prevented by occlusive membranes. These observations suggest that epidermal lipid synthesis might be related to barrier function and raised the question whether transcutaneous water flux might regulate epidermal lipogenesis. In the present study we first abrogated the barrier with acetone, and then compared the rate of repletion of stainable lipids, barrier recovery, and epidermal lipogenesis in animals covered with occlusive membranes or vapor-permeable membranes versus uncovered animals. Acetone treatment of hairless mice removed stainable neutral lipids from the stratum corneum, with repletion evident both biochemically and histochemically within 48 hr in uncovered animals. In contrast, when the animals were covered with an occlusive membrane, the usual return of stratum corneum lipids was aborted. Since application of vapor-permeable membranes allowed normal lipid repletion, occlusion alone is not responsible for the inhibition of lipid repletion. Acetone treatment also perturbed epidermal barrier function, which returned to normal in uncovered animals in parallel with the reappearance of stratum corneum lipid. However, when animals were covered with an occlusive membrane, barrier function did not recover normally. In contrast, occlusion with vapor-permeable membranes allowed barrier function to recover normally. Finally, whereas occlusive membranes prevented the characteristic increase in epidermal lipid synthesis that follows barrier perturbation, epidermal lipid synthesis was increased in animals covered with a vapor-permeable membrane. These results point to transepidermal water flux itself as the signal that regulates epidermal lipid synthesis, which is associated first with the redeposition of stratum corneum lipids and then the normalization of stratum corneum barrier function.

Lipid-related barriers and gradients in the epidermis.

The stratum corneum, once regarded as a degenerate, inconsequential tissue, is now respected as a structurally heterogeneous and metabolically active tissue. The segregation of lipids into intercellular domains, and the shift in composition from a mixture of polar lipids and neutral lipids to sphingolipids and neutral lipids have important implications for both barrier function and desquamation. Metabolic studies demonstrate the capacity of epidermis to synthesize lipids, the relative autonomy of such synthesis from extracutaneous influences, and the regulation of epidermal lipogenesis by local barrier requirements. Abundant lipid biosynthesis appears to occur in the stratum granulosum, consistent with the rapid recovery of barrier function following solvent treatment. Whereas nonpolar lipids, including sterol esters and hydrocarbons, provide a superficial barrier, sphingolipids and free sterols provide a more profound barrier. In parallel with the synthesis of lipids for barrier function, hydrolysis of phospholipids, glycolipids, and cholesterol sulfate occurs in the outer epidermis leading to a more hydrophobic lipid mixture with the evolution of broad membrane bilayers that may regulate both transcutaneous water loss and desquamation.

Relationship of epidermal lipogenesis to cutaneous barrier function.

Although the lipids of mammalian stratum corneum are known to be important for the cutaneous permeability barrier, the factors that regulate epidermal lipid biosynthesis are poorly understood. Recent studies suggest that cutaneous sterol synthesis is regulated by cutaneous barrier requirements, while the levels of circulating sterols do not play a role. Whether cutaneous barrier requirements regulate epidermal lipogenesis in general and the nature of the signal that activates the lipid biosynthetic apparatus are unknown. We determined whether alterations of the cutaneous permeability barrier, induced by treatment with a solvent (acetone), a surfactant, sodium dodecyl sulfate (SDS), or essential fatty acid deficiency (EFAD), provoked a discrete versus global stimulation of epidermal and dermal lipid biosynthesis. Acetone treatment increased epidermal, but not dermal, sterol and fatty acid biosynthesis approximately threefold over controls at 1-4 hr, which returned to normal after 12 hr. SDS treatment likewise stimulated epidermal sterol and fatty acid biosynthesis, but the increase was less dramatic than in acetone-treated animals. Since plastic occlusion blocked the expected increase in de novo lipid biosynthesis in acetone-treated animals, it is possible that water flux provides the molecular signal for de novo synthesis. Finally, EFAD mice also demonstrated enhanced epidermal sterol and fatty acid biosynthesis in comparison to normals, an effect that also was abolished when transepidermal water loss was normalized by occlusion, despite the presence of ongoing EFAD. These results demonstrate that disruption of the cutaneous permeability barrier stimulates a parallel, global boost in both sterol and fatty acid biosynthesis that is limited to the epidermis. Since such stimulation is reversed by restoration of barrier function, transcutaneous water gradients may regulate epidermal lipogenesis.

Abnormal Lipogenesis in Thyroid Hormone-Deficient Epidermis

Striking skin changes can accompany hypothyroidism, among them a scaly ichthyosis. The pathogenesis of these disorders is unknown. Since altered sterol metabolism has been associated with other scaling dermatoses, we tested the hypothesis that altered epidermal lipogenesis may accompany hypothyroidism and induce the observed scaling. Thyroidectomized (TX) rats were sacrificed 53 days postthyroidectomy, and the rate of incorporation of the radiolabeled precursor, [14C]acetate, into epidermal lipids was determined. Approximately 2-fold decreases in incorporation of precursor into both polar and neutral lipids were observed in the TX epidermis; the most significant decreases, however, were in the neutral lipids, particularly the sterol and sterol-ester moieties. Total cholesterol pool size was also reduced in the TX epidermis. Similar decreases in sterol biosynthesis were noted in human keratinocytes cultivated in medium devoid of thyroid hormone. These findings demonstrate that lipid metabolism, and notably sterol synthesis, is altered in epidermal keratinocytes deprived of thyroid hormone, and suggest that, as in other scaling disorders, this abnormal sterologenesis may lead to the clinically observed ichthyosis that can accompany hypothyroidism.

Isoniazid-Induced Pellagra

To the Editor.— In a communication on the subject of isoniazid-induced pellagra, 1 we mentioned preliminary evidence that rats receiving isoniazid showed evidence of increased epidermal lipid biosynthesis. This result was of interest first because isoniazid, as an antagonist of the hypocholesterolemic agent niacin, might be expected if anything to stimulate lipid and especially sterol biosynthesis. Second, increased levels of total epidermal lipogenesis and of sterol biosynthesis relative to other lipids are found in lesions of psoriasis and lichen simplex 2 Present Results With Higher Doses of Isoniazid Group Epidermal Lipogenesis (dpm* 3-mm Biopsy Specimen) Sterols (% of Total Lipid Labeling) Controls (N = 8) 6,620 ± 380 6.22 ± 0.69 Isoniazid-treated, 20 mg/kg/ day for 8 wk (N = 8) 7,010 ± 630 4.93 ± 0.46 Isoniazid-treated 40 mg/kg/ day for 8 wk (N = 7) 5,420 ± 540 5.50 ± 0.40 *dpm indicates disintegrations per minute. and it seemed possible that a

Sebaceous lipogenesis in human skin. Variability with age and with severity of acne.

Lipogenesis from [14C] glucose was measured in skin biopsies from the shoulder-blade region of forty-two male subjects. In the acne age range, dermal lipogenesis showed an upward trend with increasing severity of acne; a similar trend was found in forehead sebum excretion rate, but no correlation was obvious between dermal lipogenesis (back) and sebum secretion rate (forehead) in the same subject. In older subjects, dermal lipogenesis was significantly increased in those with a past history of severe acne. At high rates of dermal lipogenesis there was a small but significant increase in wax ester labelling relative to triglyceride and squalene. No increase was found in squalene labelling relative to other lipids, either with increasing lipogenic rate or in severe acne. Dermal and epidermal lipogenesis rates showed no correlation with age. In dermis, however, there was a decrease in wax ester labelling relative to triglyceride, and a marked decrease in squalene labelling relative to both triglyceride and wax esters, with increasing age.