Regulation of ABCA1 expression in human keratinocytes and murine epidermis

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359

366

The permeability barrier is required for terrestrial life and is localized to the stratum corneum, where extracellular lipid membranes inhibit water movement. The lipids that constitute the extracellular matrix have a unique composition and are 50% ceramides, 25% cholesterol, and 15% free fatty acids. Essential fatty acid deficiency results in abnormalities in stratum corneum structure function. The lipids are delivered to the extracellular space by the secretion of lamellar bodies, which contain phospholipids, glucosylceramides, sphingomyelin, cholesterol, and enzymes. In the extracellular space, the lamellar body lipids are metabolized by enzymes to the lipids that form the lamellar membranes. The lipids contained in the lamellar bodies are derived from both epidermal lipid synthesis and extracutaneous sources. Inhibition of cholesterol, fatty acid, ceramide, or glucosylceramide synthesis adversely affects lamellar body formation, thereby impairing barrier homeostasis. Studies have further shown that the elongation and desaturation of fatty acids is also required for barrier homeostasis. The mechanisms that mediate the uptake of extracutaneous lipids by the epidermis are unknown, but keratinocytes express LDL and scavenger receptor class B type 1, fatty acid transport proteins, and CD36. Topical application of physiologic lipids can improve permeability barrier homeostasis and has been useful in the treatment of cutaneous disorders.-Feingold, K. R. The role of epidermal lipids in cutaneous permeability barrier homeostasis. J. Lipid Res.

Section: Jlr: Are the Apolipoproteins That Interact With Lipoprotein mentioning

confidence: 84%

Section: Jlr: Are the Apolipoproteins That Interact With Lipoprotein mentioning

confidence: 99%

Thematic review series: Skin Lipids. The role of epidermal lipids in cutaneous permeability barrier homeostasis

Feingold

2007

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359

366

“…ABCA1 is expressed in human keratinocytes and murine epidermis, and LXR activation markedly increases ABCA1 mRNA and protein levels in keratinocytes and mouse epidermis (87). In addition, activators of PPARa and PPARb/y, but not PPARg, also increase ABCA1 expression in human keratinocytes (87).…”

Section: Abca1mentioning

confidence: 99%

Thematic Review Series: Skin Lipids. Peroxisome proliferator-activated receptors and liver X receptors in epidermal biology

Schmuth

Jiang

Dubrac

et al. 2008

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183

160

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 PPARa, -b/d, or -g 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

“…The effl ux of cholesterol from cells is mediated by ABCA1 (16)(17)(18). Previously, we reported that ABCA1 is expressed in cultured human keratinocytes (CHKs) and murine epidermis, and that liver X receptor (LXR) activation markedly stimulates ABCA1 mRNA and protein levels in CHKs and mouse epidermis ( 19 ). Similar to LXR, activation of other nuclear receptors, including peroxisome proliferatoractivated receptor-␣ (PPAR-␣ ), PPAR-␤ / ␦ , and RXR, also increase ABCA1 expression in CHKs ( 19 ).…”

Section: Microscopy and Immunohistochemistrymentioning

confidence: 99%

“…Previously, we reported that ABCA1 is expressed in cultured human keratinocytes (CHKs) and murine epidermis, and that liver X receptor (LXR) activation markedly stimulates ABCA1 mRNA and protein levels in CHKs and mouse epidermis ( 19 ). Similar to LXR, activation of other nuclear receptors, including peroxisome proliferatoractivated receptor-␣ (PPAR-␣ ), PPAR-␤ / ␦ , and RXR, also increase ABCA1 expression in CHKs ( 19 ). Additionally, increases in cholesterol levels in keratinocytes induced by LDL or mevalonate stimulate ABCA1 expression, while inhibiting cholesterol synthesis with statins, or CS decreases ABCA1 expression in CHKs ( 19 ).…”

Section: Microscopy and Immunohistochemistrymentioning

confidence: 99%

Regulation of ABCG1 expression in human keratinocytes and murine epidermis

Jiang

Lü

Tarling

et al. 2010

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Journal of Lipid ResearchCholesterol levels are tightly regulated in cells, and maintenance of cholesterol homeostasis is of particular importance in keratinocytes/epidermis. In addition to being an essential component of all cell membranes, cholesterol is required in differentiated keratinocytes to form lamellar bodies (LBs) ( 1, 2 ). Secretion of these unique organelles delivers lipids, including cholesterol, which mediate permeability barrier function, to the extracellular spaces of the stratum corneum (SC) ( 2 ). The ability to limit the transcutaneous movement of water and electrolytes is required for terrestrial life. Although cholesterol synthesis rates are high under basal conditions, following permeability barrier disruption, epidermal cholesterol synthesis increases ( 3 ), as do the levels of receptors such as the LDL receptor and scavenger receptor class B, member 1 that enhance the uptake of cholesterol into keratinocytes ( 4, 5 ). Inhibition of cholesterol synthesis perturbs permeability barrier function ( 6 ), and a selective deficiency in cholesterologenesis largely accounts for the barrier abnormality in chronologically aged epidermis ( 7,8 ). Cholesterol is also the precursor of an important bioregulatory molecule in keratinocytes, cholesterol sulfate (CS), which regulates epidermal keratinocyte differentiation ( 9-11 ) and corneocyte desquamation by diverse mechanisms ( 12, 13 ).Abstract ABCG1, a member of the ATP binding cassette superfamily, facilitates the effl ux 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 proliferatoractivated receptor-␦ (PPAR-␦ ) activators, cellular sterol levels, and acute barrier disruption. Both LXR and PPAR-␦ activators markedly stimulate ABCG1 expression in a doseand time-dependent fashion. PPAR-␥ activators also increase ABCG1 expression, but to a lesser degree. In contrast, activators of PPAR-␣ , 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