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ABCA12 maintains the epidermal lipid permeability barrier by facilitating formation of ceramide linoleic esters

Ying Zuo1, Debbie Z Zhuang, Rong Han

  • 1Lipid Metabolism Unit, Department of Medicine, Center for Computational & Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

The Journal of Biological Chemistry
|October 30, 2008
PubMed

Insights

Harlequin ichthyosis, a severe skin disorder, results from mutations in the ABCA12 gene. ABCA12 protein is crucial for generating essential skin barrier lipids, omega-hydroxyceramides, and their esters.

Area of Science:

  • Dermatology
  • Genetics
  • Molecular Biology

Background:

  • Harlequin ichthyosis is a severe congenital skin disorder characterized by epidermal hyperkeratosis and a compromised skin permeability barrier.
  • Mutations in the ATP-binding cassette transporter A12 (ABCA12) gene are linked to harlequin ichthyosis, but its precise molecular function remains unclear.

Purpose of the Study:

  • To investigate the molecular function of ABCA12 in skin barrier formation.
  • To determine the impact of Abca12 deficiency on skin structure, function, and lipid composition.

Main Methods:

  • Generation and analysis of Abca12 null mice (Abca12-/-).
  • Assessment of skin thickness, water evaporation, cell proliferation, and desquamation.
  • Electron microscopy to evaluate the lamellar permeability barrier.
  • Analysis of skin lipid content, specifically ceramide and ester composition.

Main Results:

  • Abca12-/- mice exhibit a thickened epidermis and die shortly after birth due to rapid water loss.
  • The epidermal thickening is attributed to a lack of desquamation, not increased keratinocyte proliferation.
  • Abca12-/- skin shows a defective lamellar permeability barrier with reduced linoleic esters of long-chain omega-hydroxyceramides and increased glucosyl ceramide precursors.

Conclusions:

  • ABCA12 protein activity is essential for the proper generation of long-chain ceramide esters.
  • These ceramide esters are critical for establishing a functional skin permeability barrier and normal skin structure.
  • Defective ABCA12 function leads to harlequin ichthyosis by impairing skin barrier lipid synthesis.

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