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    A Mouse Model of Harlequin Ichthyosis Delineates a Key Role for Abca12 in Lipid Homeostasis

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    Author
    Smyth, I; Hacking, DF; Hilton, AA; Mukhamedova, N; Meikle, PJ; Ellis, S; Slattery, K; Collinge, JE; de Graaf, CA; Bahlo, M; ...
    Date
    2008-09-01
    Source Title
    PLoS Genetics
    Publisher
    PUBLIC LIBRARY SCIENCE
    University of Melbourne Author/s
    Kile, Benjamin; Hilton, Douglas; Ellis, Sarah; Meikle, Peter; de Graaf, Carolyn; Bahlo, Melanie
    Affiliation
    School of BioSciences
    Medical Biology (W.E.H.I.)
    Sir Peter MacCallum Department of Oncology
    Bio21
    School of Mathematics and Statistics
    Metadata
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    Document Type
    Journal Article
    Citations
    Smyth, I., Hacking, D. F., Hilton, A. A., Mukhamedova, N., Meikle, P. J., Ellis, S., Slattery, K., Collinge, J. E., de Graaf, C. A., Bahlo, M., Sviridov, D., Kile, B. T. & Hilton, D. J. (2008). A Mouse Model of Harlequin Ichthyosis Delineates a Key Role for Abca12 in Lipid Homeostasis. PLOS GENETICS, 4 (9), https://doi.org/10.1371/journal.pgen.1000192.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/265122
    DOI
    10.1371/journal.pgen.1000192
    Abstract
    Harlequin Ichthyosis (HI) is a severe and often lethal hyperkeratotic skin disease caused by mutations in the ABCA12 transport protein. In keratinocytes, ABCA12 is thought to regulate the transfer of lipids into small intracellular trafficking vesicles known as lamellar bodies. However, the nature and scope of this regulation remains unclear. As part of an original recessive mouse ENU mutagenesis screen, we have identified and characterised an animal model of HI and showed that it displays many of the hallmarks of the disease including hyperkeratosis, loss of barrier function, and defects in lipid homeostasis. We have used this model to follow disease progression in utero and present evidence that loss of Abca12 function leads to premature differentiation of basal keratinocytes. A comprehensive analysis of lipid levels in mutant epidermis demonstrated profound defects in lipid homeostasis, illustrating for the first time the extent to which Abca12 plays a pivotal role in maintaining lipid balance in the skin. To further investigate the scope of Abca12's activity, we have utilised cells from the mutant mouse to ascribe direct transport functions to the protein and, in doing so, we demonstrate activities independent of its role in lamellar body function. These cells have severely impaired lipid efflux leading to intracellular accumulation of neutral lipids. Furthermore, we identify Abca12 as a mediator of Abca1-regulated cellular cholesterol efflux, a finding that may have significant implications for other diseases of lipid metabolism and homeostasis, including atherosclerosis.

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