First Author | Haller JF | Year | 2014 |
Journal | J Lipid Res | Volume | 55 |
Issue | 3 | Pages | 493-503 |
PubMed ID | 24293640 | Mgi Jnum | J:208287 |
Mgi Id | MGI:5562607 | Doi | 10.1194/jlr.M044941 |
Citation | Haller JF, et al. (2014) Endogenous beta-glucocerebrosidase activity in Abca12(-)/(-)epidermis elevates ceramide levels after topical lipid application but does not restore barrier function. J Lipid Res 55(3):493-503 |
abstractText | 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 beta-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 significantly reduce trans-epidermal 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. |