Thematic review series: skin lipids. Peroxisome proliferator-activated receptors and liver X receptors in epidermal biology

The epidermis is a very active site of lipid metabolism, and all peroxisome proliferator-activated receptor (PPAR) and liver X receptor (LXR) isoforms are expressed in the epidermis. Activation of PPARalpha, -beta/delta, or -gamma or LXRs stimulates keratinocyte differentiation. Additionally, activation of these receptors also improves permeability barrier homeostasis by a number of mechanisms, including stimulating epidermal lipid synthesis, increasing lamellar body formation and secretion, and increasing the activity of enzymes required for the extracellular processing of lipids in the stratum corneum, leading to the formation of lamellar membranes that mediate permeability barrier function. The stimulation of keratinocyte differentiation and permeability barrier formation also occurs during fetal development, resulting in accelerated epidermal development. PPAR and LXR activation regulates keratinocyte proliferation and apoptosis, and studies have shown that these receptors play a role in cutaneous carcinogenesis. Lastly, PPAR and LXR activation is anti-inflammatory, reducing inflammation in animal models of allergic and irritant contact dermatitis. Because of their broad profile of beneficial effects on skin homeostasis, PPAR and LXR have great potential to serve as drug targets for common skin diseases such as psoriasis, atopic dermatitis, and skin cancer.     

Regulation of ABCA1 expression in human keratinocytes and murine epidermis

Keratinocytes require abundant cholesterol for cutaneous permeability barrier function; hence, the regulation of cholesterol homeostasis is of great importance. ABCA1 is a membrane transporter responsible for cholesterol efflux and plays a pivotal role in regulating cellular cholesterol levels. We demonstrate that ABCA1 is expressed in cultured human keratinocytes (CHKs) and murine epidermis. Liver X receptor (LXR) activation markedly stimulates ABCA1 mRNA and protein levels in CHKs and mouse epidermis. In addition to LXR, activators of peroxisome proliferator-activated receptor (PPAR)alpha, PPARbeta/delta, and retinoid X receptor (RXR), but neither PPARgamma nor retinoic acid receptor, also increase ABCA1 expression in CHKs. Increases in cholesterol supply induced by LDL or mevalonate stimulate ABCA1 expression, whereas inhibiting cholesterol synthesis with statins or cholesterol sulfate decreases ABCA1 expression in CHKs. After acute permeability barrier disruption by either tape-stripping or acetone treatment, ABCA1 expression declines, and this attenuates cellular cholesterol efflux, making more cholesterol available for regeneration of the barrier. In addition, during fetal epidermal development, ABCA1 expression decreases at days 18-22 of gestation (term = 22 days), leaving more cholesterol available during the critical period of barrier formation. Together, our results show that ABCA1 is expressed in keratinocytes, where it is negatively regulated by a decrease in cellular cholesterol levels or altered permeability barrier requirements and positively regulated by activators of LXR, PPARs, and RXR or increases in cellular cholesterol levels.     

Regulation of ABCG1 expression in human keratinocytes and murine epidermis

ABCG1, a member of the ATP binding cassette superfamily, facilitates the efflux of cholesterol from cells to HDL. In this study, we demonstrate that ABCG1 is expressed in cultured human keratinocytes and murine epidermis, and induced during keratinocyte differentiation, with increased levels in the outer epidermis. ABCG1 is regulated by liver X receptor (LXR) and peroxisome proliferator-activated receptor-δ (PPAR-δ) activators, cellular sterol levels, and acute barrier disruption. Both LXR and PPAR-δ activators markedly stimulate ABCG1 expression in a dose- and time-dependent fashion. PPAR-γ activators also increase ABCG1 expression, but to a lesser degree. In contrast, activators of PPAR-α, retinoic acid receptor, retinoid X receptor, and vitamin D receptor do not alter ABCG1 expression. In response to increased intracellular sterol levels, ABCG1 expression increases, whereas inhibition of cholesterol biosynthesis decreases ABCG1 expression. In vivo, ABCG1 is stimulated 3–6 h after acute barrier disruption by either tape stripping or acetone treatment, an increase that can be inhibited by occlusion, suggesting a potential role of ABCG1 in permeability barrier homeostasis. Although Abcg1-null mice display normal epidermal permeability barrier function and gross morphology, abnormal lamellar body (LB) contents and secretion leading to impaired lamellar bilayer formation could be demonstrated by electron microscopy, indicating a potential role of ABCG1 in normal LB formation and secretion.     

Resistance to Water Diffusion in the Stratum Corneum Is Depth-Dependent

The stratum corneum (SC) provides a permeability barrier that limits the inflow and outflow of water. The permeability barrier is continuously and dynamically formed, maintained, and degraded along the depth, from the bottom to the top, of the SC. Naturally, its functioning and structure also change dynamically in a depth-dependent manner. While transepidermal water loss is typically used to assess the function of the SC barrier, it fails to provide any information about the dynamic mechanisms that are responsible for the depth-dependent characteristics of the permeability barrier. This paper aims to quantitatively characterize the depth-dependency of the permeability barrier using in vivo non-invasive measurement data for understanding the underlying mechanisms for barrier formation, maintenance, and degradation. As a framework to combine existing experimental data, we propose a mathematical model of the SC, consisting of multiple compartments, to explicitly address and investigate the depth-dependency of the SC permeability barrier. Using this mathematical model, we derive a measure of the water permeability barrier, i.e. resistance to water diffusion in the SC, from the measurement data on transepidermal water loss and water concentration profiles measured non-invasively by Raman spectroscopy. The derived resistance profiles effectively characterize the depth-dependency of the permeability barrier, with three distinct regions corresponding to formation, maintenance, and degradation of the barrier. Quantitative characterization of the obtained resistance profiles allows us to compare and evaluate the permeability barrier of skin with different morphology and physiology (infants vs adults, different skin sites, before and after application of oils) and elucidates differences in underlying mechanisms of processing barriers. The resistance profiles were further used to predict the spatial-temporal effects of skin treatments by in silico experiments, in terms of spatial-temporal dynamics of percutaneous water penetration.     

Ascorbate reverses high glucose- and RAGE-induced leak of the endothelial permeability barrier

High glucose concentrations due to diabetes increase leakage of plasma constituents across the endothelial permeability barrier. We sought to determine whether vitamin C, or ascorbic acid (ascorbate), could reverse such high glucose-induced increases in endothelial barrier permeability. Human umbilical vein endothelial cells and two brain endothelial cell lines cultured at 25 mM glucose showed increases in endothelial barrier permeability to radiolabeled inulin compared to cells cultured at 5 mM glucose. Acute loading of the cells for 30–60 min with ascorbate before the permeability assay prevented the high glucose-induced increase in permeability and decreased basal permeability at 5 mM glucose. High glucose-induced barrier leakage was mediated largely by activation of the receptor for advanced glycation end products (RAGE), since it was prevented by RAGE blockade and mimicked by RAGE ligands. Intracellular ascorbate completely prevented RAGE ligand-induced increases in barrier permeability. The high glucose-induced increase in endothelial barrier permeability was also acutely decreased by several cell-penetrant antioxidants, suggesting that at least part of the ascorbate effect could be due to its ability to act as an antioxidant.     

Permeability of the Isolated Toad Bladder to Solutes and Its Modification by Vasopressin

Measurements have been made of the permeability of the isolated urinary bladder of the toad to a number of small solute molecules, in the presence and absence of vasopressin. Vasopressin has a strikingly specific effect on increasing permeability of the bladder to a group of small, uncharged amides and alcohols while penetration by other small molecules and ions is unaffected. The movement of urea is passive, as indicated by equal flux rates in the two directions. The reflection coefficients for chloride and thiourea indicate a high degree of impermeability of the bladder to these solutes even in the presence of large net movements of water. The low concentration of thiourea in the tissue water when this compound is added to the mucosal bathing medium indicates that the major permeability barrier to thiourea is at the mucosal surface of the bladder. The findings can be accounted for by a double permeability barrier consisting of a fine selective diffusion barrier and a porous barrier in series. The former would constitute the permeability barrier to most small solutes while the latter would be the rate-limiting barrier for water and the amides. It would be the porous barrier which is affected by vasopressin. Reasons are presented which require both barriers to be contained in or near the plasma membrane at the mucosal surface of the bladder.     

Lifelong Consumption of Sodium Selenite: Gender Differences on Blood–Brain Barrier Permeability in Convulsive,Hypoglycemic Rats

The aim of this study was to compare the effects of hypoglycemia and induced convulsions on the blood-brain barrier permeability in rats with or without lifelong administration of sodium selenite. There is a significant decrease of the blood-brain barrier permeability in three brain regions of convulsive, hypoglycemic male rats treated with sodium selenite when compared to sex-matched untreated rats (p<0.05), but the decrease was not significant in female rats (p>0.05). The blood-brain barrier permeability of the left and right hemispheres of untreated, moderately hypoglycemic convulsive rats of both genders was better than their untreated counterparts (p<0.05). Our results suggest that moderate hypoglycemia and lifelong treatment with sodium selenite have a protective effect against blood-brain barrier permeability during convulsions and that the effects of sodium selenite are gender-dependent.     

The nuclear barrier is structurally and functionally highly responsive to glucocorticoids

Nuclear pore complexes mediate and control transport between the cytosol and the nucleus. They form a highly selective and, thus, tight nuclear barrier between these compartments. The nuclear barrier provides the cell with the opportunity to control access to its DNA, a defining feature of eukaryotes. The tightness of the nuclear barrier is therefore physiologically pivotal and any remarkable change in its structure and permeability can prove pathophysiological, e.g. as a result of viral attack. However, there is accumulating evidence that nuclear barrier structure and permeability are highly responsive to hydrophobic cargos of crucial physiological and therapeutic relevance, glucocorticoids (steroid hormones). The present review highlights the glucocorticoid-induced effects on the nuclear barrier structure and permeability concluding that they are physiologically essential to mediate glucocorticoid action.