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Int J Biol Sci 2007; 3(2):120-128. doi:10.7150/ijbs.3.120

Research Paper

Depletion of ceramides with very long chain fatty acids causes defective skin permeability barrier function, and neonatal lethality in ELOVL4 deficient mice

Wenmei Li1, Roger Sandhoff2, Mari Kono1, Patricia Zerfas3, Vickie Hoffmann3, Bryan Char-Hoa Ding1, Richard L. Proia1, Chu-Xia Deng1

1. Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA.
2. Cellular and Molecular Pathology (E090), German Cancer Research Center, Heidelberg, Germany.
3. Division of Veterinary Resources, Office of Research Services, National Institutes of Health, Bethesda, MD 20892, USA.


Very long chain fatty acids (VLCFA), either free or as components of glycerolipids and sphingolipids, are present in many organs. Elongation of very long chain fatty acids-4 (ELOVL4) belongs to a family of 6 members of putative fatty acid elongases that are involved in the formation of VLCFA. Mutations in ELOVL4 were found to be responsible for an autosomal dominant form of Stargardt's-like macular dystrophy (STGD3) in human. We have previously disrupted the mouse Elovl4 gene, and found that Elovl4+/- mice were developmentally normal, suggesting that haploinsufficiency of ELOVL4 is not a cause for the juvenile retinal degeneration in STGD3 patients. However, Elovl4-/- mice died within several hours of birth for unknown reason(s). To study functions of ELOVL4 further, we have explored the causes for the postnatal lethality in Elovl4-/- mice. Our data indicated that the mutant mice exhibited reduced thickness of the dermis, delayed differentiation of keratinocytes, and abnormal structure of the stratum corneum. We showed that all Elovl4-/- mice exhibited defective skin water permeability barrier function, leading to the early postnatal death. We further showed that the absence of ELOVL4 results in depletion in the epidermis of ceramides with ω-hydroxy very long chain fatty acids (≥C28) and accumulation of ceramides with non ω-hydroxy fatty acids of C26, implicating C26 fatty acids as possible substrates of ELOVL4. These data demonstrate that ELOVL4 is required for VLCFA synthesis that is essential for water permeability barrier function of skin.

Keywords: ELOVL4, lipid, epidermis, keratinocyte differentiation, stratum corneum

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How to cite this article:
Li W, Sandhoff R, Kono M, Zerfas P, Hoffmann V, Ding BCH, Proia RL, Deng CX. Depletion of ceramides with very long chain fatty acids causes defective skin permeability barrier function, and neonatal lethality in ELOVL4 deficient mice. Int J Biol Sci 2007; 3(2):120-128. doi:10.7150/ijbs.3.120. Available from