Alteration of epidermal lipid composition as a result of deficiency in the magnesium transporter Nipal4

Lipids in the stratum corneum play an important role in the formation of the skin permeability barrier. The causative gene for congenital ichthyosis, NIPAL4, encodes a Mg2+ transporter and is involved in increases in intracellular Mg2+ concentrations that depend on keratinocyte differentiation. However, the role of this increased Mg2+ concentration in skin barrier formation and its effect on the lipid composition of the stratum corneum has remained largely unknown. Therefore, in the present study, we performed a detailed analysis of epidermal lipids in Nipal4 KO mice via TLC and MS. Compared with WT mice, the Nipal4 KO mice showed compositional changes in many ceramide classes (including decreases in ω-O-acylceramides and increases in ω-hydroxy ceramides), together with increases in ω-hydroxy glucosylceramides, triglycerides, and FFAs and decreases in ω-O-acyl hydroxy FAs containing a linoleic acid. We also found increases in unusual ω-O-acylceramides containing oleic acid or palmitic acid in the KO mice. However, there was little change in levels of cholesterol or protein-bound ceramides. The TLC analysis showed that some unidentified lipids were increased, and the MS analysis showed that these were special ceramides called 1-O-acylceramides. These results suggest that elevated Mg2+ concentrations in differentiated keratinocytes affect the production of various lipids, resulting in the lipid composition necessary for skin barrier formation.