Accumulation of protein‐bound epidermal glucosylceramides in β‐glucocerebrosidase deficient type 2 Gaucher mice

Doering, Thomas; Proia, Richard L.; Sandhoff, Konrad

doi:10.1016/s0014-5793(99)00274-4

Cited by 91 publications

(77 citation statements)

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“…Although it is formally possible that ABCA12 could play a role in transporting ␤-glucocerebrosidase rather than its substrate lipids, studies in animals either lacking the enzyme in the skin or treated with an enzyme inhibitor have reported no disruption of the epidermal lamellar body structure (38,39). Additionally, loss of ␤-glucocerebrosidase, or its activator Saposin-C caused a different spectrum of ceramide and glucosylceramide alterations in the skin than those we report here in the Abca12 Ϫ/Ϫ mice (40,41). Thus, we believe that current data are most consistent with a model that posits ABCA12 functions as a lipid transporter that is required for the transport of a specialized class of ceramides into the lamellar body.…”

Section: That Their Abca12mentioning

confidence: 49%

ABCA12 Maintains the Epidermal Lipid Permeability Barrier by Facilitating Formation of Ceramide Linoleic Esters

Zuo

Zhuang

Han

et al. 2008

Journal of Biological Chemistry

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Harlequin ichthyosis is a congenital scaling syndrome of the skin in which affected infants have epidermal hyperkeratosis and a defective permeability barrier. Mutations in the gene encoding a member of the ABCA transporter family, ABCA12, have been linked to harlequin ichthyosis, but the molecular function of the protein is unknown. To investigate the activity of ABCA12, we generated Abca12 null mice and analyzed the impact on skin function and lipid content. Abca12 ؊/؊ mice are born with a thickened epidermis and die shortly after birth, as water rapidly evaporates from their skin. In vivo skin proliferation measurements suggest a lack of desquamation of the skin cells, rather than enhanced proliferation of basal layer keratinocytes, accounts for the 5-fold thickening of the Abca12 ؊/؊ stratum corneum. Electron microscopy revealed a loss of the lamellar permeability barrier in Abca12 ؊/؊ skin. This was associated with a profound reduction in skin linoleic esters of long-chain -hydroxyceramides and a corresponding increase in their glucosyl ceramide precursors. Because -hydroxyceramides are required for the barrier function of the skin, these results establish that ABCA12 activity is required for the generation of longchain ceramide esters that are essential for the development of normal skin structure and function. Harlequin ichthyosis (HI)2 is the most severe of the congenital, autosomal ichthyoses with affected infants developing large, hard, plate-like scales over all of their epidermal surfaces. Abnormal temperature regulation, enhanced water loss, and bacterial super-infections develop as a consequence of defects in the barrier functions of the skin, making survival through the neonatal period difficult. In recent years, several groups have linked HI, as well as less severe forms of ichthyosis, to mutations in the gene encoding a member of the ABCA family of transporters, ABCA12 (1-7). The A class of ABC transporters consists of at least eleven transporters in humans and mice, several of which are known to play critical roles in human disease. ABCA1, the best studied of the proteins, is causally linked to Tangier disease and is associated with defective phospholipid and cholesterol transport from intracellular lipid stores to the major amphipathic helical apoprotein of high density lipoprotein, apolipoprotein A-1 (8 -11). ABCA3 mutations cause a form of neonatal respiratory failure that arises from a failure to transport pulmonary phospholipids comprising surfactant from their storage site in the lamellar bodies of alveolar type II cells to the alveolar space (12)(13)(14). This transport process, like the one involving ABCA1, appears to depend on the lipidation of an acceptor amphipathic helical protein, surfactant protein B (15, 16). ABCA4 causes Stargadt macular degeneration and visual loss that is associated with a defect in the transport of phosphatidylethanolamine-retinylidene adducts out of retinal pigment epithelial cells (17)(18)(19). The role of any acceptor proteins in this process is unknown. T...

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Section: That Their Abca12mentioning

confidence: 49%

ABCA12 Maintains the Epidermal Lipid Permeability Barrier by Facilitating Formation of Ceramide Linoleic Esters

Zuo

Zhuang

Han

et al. 2008

Journal of Biological Chemistry

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“…In this study, we characterized the development of epidermal lipid profiles during embryonic SC formation underlying the acquisition of a competent barrier to water loss. It has been shown that the processing of epidermal GlcCer to Cer is a prerequisite for barrier formation (2)(3)(4). In these studies, transgenic mice were used that were deficient in either GlcCerase or sphingolipid activator proteins required for enzymatic deglycosylation of GlcCer.…”

Section: Discussionmentioning

confidence: 99%

“…This corneocyte lipid envelope is thought to be essential for the interaction of highly crosslinked proteins of the CE with the extracellular lipid matrix (13). The formation of the corneocyte lipid envelope requires GlcCer(EOS), which is transacylated either prior or after deglycosylation to CE proteins (3,4). Most interestingly, not only the epidermal level of GlcCer(EOS) but also of corresponding Cer(EOS) decreased during gestational barrier formation indicating that a pool of both GlcCer(EOS) and Cer(EOS) is recruited for the formation of the corneocyte lipid envelope.…”

Section: Discussionmentioning

confidence: 99%

“…Using transgenic mice it has been shown that this enzyme is required for skin barrier formation (2,3). Postsecretory processing of GlcCers to a family of ceramides (Cers) requires GlcCerase to be assisted by a sphingolipid activator protein (4).…”

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confidence: 99%

“…The predominant chain lengths of these -hydroxy fatty acids are 32-carbon saturated as well as 32-and 34-carbon monounsaturated species that are acylated with linoleic acid via the -OH position. This unique epidermal lipid has been shown to be important for both the lamellar organization of the barrier lipids (6,7) and for the formation of a lipid monolayer covalently bound to surface proteins of the corneocytes (3,8,9).…”

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Sphingolipid metabolism during epidermal barrier development in mice

Doering

Brade

Sandhoff

2002

Journal of Lipid Research

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In rodents, a competent skin barrier to water loss is formed within 2 or 3 days prior to birth. Acquisition of barrier function during rat gestation correlates with the formation of a stratum corneum enriched in ceramides, cholesterol, and fatty acids (Aszterbaum, M., G. K. Menon, K. R. Feingold, and M. L. Williams. 1992. Ontogeny of the epidermal barrier to water loss in the rat: correlation of function with stratum corneum structure and lipid content. Pediatr. Res. 31: 308-317). We analyzed the formation and epidermal localization of glucosylceramides during embryonic skin barrier development in Balb/c mice. Using immunohistochemistry, epidermal glucosylceramides were hardly detectable 3 days prior to birth. After further 24 h of gestation the level of glucosylceramides was maximal and decreased with increasing gestational age. In parallel, glucosylceramides were targeted to the apical side of the outermost granular keratinocyte layer. A spectrum of five distinct epidermal ceramides was present 2 days prior to birth. With ongoing gestation the composition of the ceramide fraction changed markedly. Most importantly, the level of -hydroxylated acylceramides decreased paralleled by the formation of the corneocyte lipid envelope. This structure consists of -hydroxylated ceramides and fatty acids bound to surface proteins of the corneocytes. The covalent attachment of ceramides or glucosylceramides correlated with the maturation of the stratum corneum and might contribute to its chemical and enzymatic resistance. -Doering, T., H. Brade, and K. Sandhoff. Sphingolipid metabolism during epidermal barrier development in mice.

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Lipidomics

Farwanah¹,

Kolter²

2008

Wiley Encyclopedia of Chemical Biology

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Lipids are hydrophobic or amphiphilic low‐molecular‐weight substances with a low solubility in water. Glycerophospholipids, sphingolipids, and cholesterol are the building blocks of cellular membranes, and triacylglycerols are the major molecular storage forms of metabolic energy. Various lipids serve as signaling substances either as first or second messengers in signal transduction; as autocrinic, paracrinic, or endocrinic regulators; or are covalently bound to cellular proteins. Several diseases are caused by, or at least associated with, alterations in lipid metabolism, such as inherited disorders of lipid metabolism, atherosclerosis, diabetes, obesity, or Alzheimer's disease.

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Accumulation of protein‐bound epidermal glucosylceramides in β‐glucocerebrosidase deficient type 2 Gaucher mice

Cited by 91 publications

References 15 publications

ABCA12 Maintains the Epidermal Lipid Permeability Barrier by Facilitating Formation of Ceramide Linoleic Esters

ABCA12 Maintains the Epidermal Lipid Permeability Barrier by Facilitating Formation of Ceramide Linoleic Esters

Sphingolipid metabolism during epidermal barrier development in mice

Lipidomics

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