Localization of ABCA12 from Golgi apparatus to lamellar granules in human upper epidermal keratinocytes

Sakai, Kaori; Akiyama, Masashi; Sugiyama-Nakagiri, Yoriko; McMillan, James R.; Sawamura, Daisuke; Shimizu, Hiroshi

doi:10.1111/j.1600-0625.2007.00614.x

Cited by 70 publications

(80 citation statements)

References 45 publications

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“…However, there are some notable differences in the regulation of ABCA1 and How lipids are incorporated into LBs is still largely unknown, but studies have shown that the absence of ABCA12 results in abnormal LBs and a defective permeability barrier ( 50,51 ). By yet-to-be-defi ned mechanisms, ABCA12 facilitates the transport of glucosylceramides into LBs (50)(51)(52). Of note is that similar to our observations with ABCG1, keratinocyte differentiation and PPAR and LXR activators stimulate ABCA12 expression in keratinocytes ( 30 ).…”

Section: Discussionmentioning

confidence: 99%

Regulation of ABCG1 expression in human keratinocytes and murine epidermis

Jiang

Lü

Tarling

et al. 2010

Journal of Lipid Research

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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

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Section: Discussionmentioning

confidence: 99%

Regulation of ABCG1 expression in human keratinocytes and murine epidermis

Jiang

Lü

Tarling

et al. 2010

Journal of Lipid Research

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“…Thus, stratum granulosum cells must generate all these lipids and then transport them into the LB where they can be assembled into a lamellar structure required for barrier function ( 7 ). In normal skin, ABCA12 localizes to LB ( 33 ), and keratinocytes demonstrate a widely distributed pattern of cellular GlcCer expression ( 1,12 ). In contrast, in HI skin, GlcCer fails to localize to the periphery of the keratinocyte cytoplasm ( 34 ), and there is a loss of lamellae structure in the stratum corneum and LB ( 1,(11)(12)(13).…”

Section: Downloaded Frommentioning

confidence: 99%

Endogenous β-glucocerebrosidase activity in Abca12epidermis elevates ceramide levels after topical lipid application but does not restore barrier function

Haller

Cavallaro

Hernandez

et al. 2014

Journal of Lipid Research

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Supplementary key words glucosylceramide • harlequin ichthyosis • skin permeability barrier • ABCA12 antibodyHarlequin ichthyosis (HI) is a severe autosomal recessive disease caused by mutations in the ABCA12 lipid transporter ( 1,2 ). HI patients present with a drastically hyperkeratotic epidermis and have a complete loss of the skin permeability barrier function. Poor temperature regulation, enhanced water loss, and bacterial super-infections develop as a consequence of defects in the barrier function of HI skin, making neonatal survival diffi cult without intensive treatment ( 3-6 ).The epidermis is responsible for the formation and maintenance of the skin barrier function ( 7 ). A critical component of this barrier is the extracellular lipid domains that surround the corneocytes of the stratum corneum (SC). These interstitial lipid domains are organized in lamellar structures and consist primarily of cholesterol, fatty acid, and ceramides ( 8 ). Ceramides comprise about half of the total lipids in the SC and are essential for the lamellar structure of this extracellular lipid domain ( 8-10 ). They are synthesized exclusively from glucosylceramide (GlcCer) and sphingomyelin (SM) precursors, which are generated in nucleated keratinocytes and stored in lamellar bodies (LB). As the keratinocyte matures, the contents of the LB are extruded into the interstices of the SC where the GlcCer and SM are enzymatically hydrolyzed to Cer by ␤ -glucocerebrosidase (GCase) and sphingomyelinase Abstract ABCA12 mutations disrupt the skin barrier and cause harlequin ichthyosis. We previously showed Abca12 ؊ / ؊ skin has increased glucosylceramide (GlcCer) and correspondingly lower amounts of ceramide (Cer). To examine why loss of ABCA12 leads to accumulation of GlcCer, de novo sphingolipid synthesis was assayed using [ 14 C]serine labeling in ex vivo skin cultures. A defect was found in ␤ -glucocerebrosidase (GCase) processing of newly synthesized GlcCer species. This was not due to a decline in GCase function. Abca12 ؊ / ؊ epidermis had 5-fold more GCase protein (n = 4, P < 0.01), and a 5-fold increase in GCase activity (n = 3, P < 0.05). As with Abca12 +/+ epidermis, immunostaining in null skin showed a typical interstitial distribution of the GCase protein in the Abca12 ؊ / ؊ stratum corneum. Hence, we tested whether the block in GlcCer conversion could be circumvented by topically providing GlcCer. This approach restored up to 15% of the lost Cer products of GCase activity in the Abca12 ؊ / ؊ epidermis. However, this level of barrier ceramide replacement did not signifi cantly reduce transepidermal water loss function. Our results indicate loss of ABCA12 function results in a failure of precursor GlcCer substrate to productively interact with an intact GCase enzyme, and they support a model of ABCA12 function that is critical for transporting GlcCer into lamellar bodies.

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“…The ABCA subfamily members are thought to be lipid transporters [Peelman et al, 2003]. ABCA12 was recognized as a key molecule in keratinocyte lipid transport Sakai et al, 2007]. ABCA12 is a keratinocyte transmembrane lipid transporter protein associated with lipid transport in lamellar granules to the apical surface of granular layer keratinocytes .…”

Section: Introductionmentioning

confidence: 99%

ABCA12 mutations and autosomal recessive congenital ichthyosis: A review of genotype/phenotype correlations and of pathogenetic conceptsa

2010

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Mutations in ABCA12 have been described in autosomal recessive congenital ichthyoses (ARCI) including harlequin ichthyosis (HI), congenital ichthyosiform erythroderma (CIE), and lamellar ichthyosis (LI). HI shows the most severe phenotype. CIE and LI are clinically characterized by fine, whitish scales on a background of erythematous skin, and large, thick, dark scales over the entire body without serious background erythroderma, respectively. To date, a total of 56 ABCA12 mutations have been reported in 66 ARCI families including 48 HI, 10 LI, and 8 CIE families of African, European, Pakistani/Indian, and Japanese origin (online database: http://www.derm-hokudai.jp/ABCA12/). A total of 62.5% of reported ABCA12 mutations are expected to lead to truncated proteins. Most mutations in HI are truncation mutations and homozygous or compound heterozygous truncation mutations always results in HI phenotype. In CIE families, at least one mutation on each allele is typically a missense mutation. Combinations of missense mutations in the first ATPbinding cassette of ABCA12 underlie the LI phenotype. ABCA12 is a keratinocyte lipid transporter associated with lipid transport in lamellar granules, and loss of ABCA12 function leads to a defective lipid barrier in the stratum corneum, resulting in an ichthyotic phenotype. Recent work using mouse models confirmed ABCA12 roles in skin barrier formation.

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Localization of ABCA12 from Golgi apparatus to lamellar granules in human upper epidermal keratinocytes

Cited by 70 publications

References 45 publications

Regulation of ABCG1 expression in human keratinocytes and murine epidermis

Regulation of ABCG1 expression in human keratinocytes and murine epidermis

Endogenous β-glucocerebrosidase activity in Abca12epidermis elevates ceramide levels after topical lipid application but does not restore barrier function

ABCA12 mutations and autosomal recessive congenital ichthyosis: A review of genotype/phenotype correlations and of pathogenetic conceptsa

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