title: Depletion of ceramides with very long chain fatty acids causes defective skin permeability barrier function, and neonatal lethality in ELOVL4 deficient mice.
abstract: 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 omega-hydroxy very long chain fatty acids (> or = C28) and accumulation of ceramides with non omega-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.
authors.affiliation: 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.
authors.forename: Wenmei
authors.initials: W
authors.lastname: Li
authors.forename: Roger
authors.initials: R
authors.lastname: Sandhoff
authors.forename: Mari
authors.initials: M
authors.lastname: Kono
authors.forename: Patricia
authors.initials: P
authors.lastname: Zerfas
authors.forename: Vickie
authors.initials: V
authors.lastname: Hoffmann
authors.forename: Bryan Char-Hoa
authors.initials: BC
authors.lastname: Ding
authors.forename: Richard L
authors.initials: RL
authors.lastname: Proia
authors.forename: Chu-Xia
authors.initials: CX
authors.lastname: Deng
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000502:physiology; D002518:Ceramides / Q000378:metabolism*; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D015603:Keratinocytes / Q000473:pathology / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010539:Permeability; D012867:Skin / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D012879:Skin Physiological Phenomena; D015996:Survival Rate; D013997:Time Factors; D014867:Water / Q000378:metabolism
chemical_list: D002518:Ceramides; C498834:Elovl4 protein, mouse; D005136:Eye Proteins; D005227:Fatty Acids; D008565:Membrane Proteins; D014867:Water