Impaired Epidermal Permeability Barrier in Mice Lacking Elovl1, the Gene Responsible for Very-Long-Chain Fatty Acid Production

Abstract

The sphingolipid backbone ceramide (Cer) is a major component of lipid lamellae in the stratum corneum of epidermis and has a pivotal role in epidermal barrier formation. Unlike Cers in other tissues, Cers in epidermis contain extremely long fatty acids (FAs). Decreases in epidermal Cer levels, as well as changes in their FA chain lengths, cause several cutaneous disorders. However, the molecular mechanisms that produce such extremely long Cers and determine their chain lengths are poorly understood. We generated mice deficient in the Elovl1 gene, which encodes the FA elongase responsible for producing C₂₀ to C₂₈ FAs. Elovl1 knockout mice died shortly after birth due to epidermal barrier defects. The lipid lamellae in the stratum corneum were largely diminished in these mice. In the epidermis of the Elovl1-null mice, the levels of Cers with ≥C₂₆ FAs were decreased, while those of Cers with ≤C₂₄ FAs were increased. In contrast, the levels of C₂₄ sphingomyelin were reduced, accompanied by an increase in C₂₀ sphingomyelin levels. Two ceramide synthases, CerS2 and CerS3, expressed in an epidermal layer-specific manner, regulate Elovl1 to produce acyl coenzyme As with different chain lengths. Elovl1 is a key determinant of epidermal Cer chain length and is essential for permeability barrier formation.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00192-13.

ACKNOWLEDGMENTS

We are grateful to E. A. Sweeney for scientific editing of the manuscript. We thank Kosuke Yusa and Junji Takeda (Osaka University) for kindly providing plasmids for BAC recombineering. We thank Yukiko Mizutani (Nagoya University) and Yasuyuki Igarashi (Hokkaido University) for kindly providing the p3×FLAG-CERS2 and p3×FLAG-CERS3 plasmids. The CAG-Cre mouse was generated by Masaru Okabe (Osaka University) and provided by the Riken BRC through the National Bio-Resource Project of the MEXT, Japan.

This work was supported by a Grant-in-Aid for Scientific Research (B) (23370057) to A.K. and a Grant-in-Aid for Scientific Research (C) (24590073) to T.S. from the Japan Society for the Promotion of Science.

We declare that we have no conflicts of interest.