Abstract
Fatty acid transport protein 4 (FATP4) is an acyl-CoA synthetase that is required for normal permeability barrier in mammalian skin. FATP4 (SLC27A4) mutations cause ichthyosis prematurity syndrome, a nonlethal disorder. In contrast, Fatp4−/− mice die neonatally from a defective barrier. Here we used electron microscopy and lipidomics to characterize defects in Fatp4−/− mice. Mutants showed lamellar body, corneocyte lipid envelope, and cornified envelope abnormalities. Lipidomics identified two lipids previously speculated to be present in mouse epidermis, sphingosine β-hydroxyceramide and monoacylglycerol; mutants displayed decreased proportions of these and the two ceramide classes that carry ultralong-chain, amide-linked fatty acids (FAs) thought to be critical for barrier function, unbound ω-O-acylceramide and bound ω-hydroxyceramide, the latter constituting the major component of the corneocyte lipid envelope. Other abnormalities included elevated amounts of sphingosine α-hydroxyceramide, phytosphingosine non-hydroxyceramide, and 1-O-acylceramide. Acyl chain length alterations in ceramides also suggested roles for FATP4 in esterifying saturated non-hydroxy and β-hydroxy FAs with at least 25 carbons and saturated or unsaturated ω-hydroxy FAs with at least 30 carbons to CoA. Our lipidomic analysis is the most thorough such study of the Fatp4−/− mouse skin barrier to date, providing information about how FATP4 can contribute to barrier function by regulating fatty acyl moieties in various barrier lipids.
Highlights
Mammalian skin defends against biological, chemical, and mechanical assaults and acts as a barrier to prevent water loss
Ultrastructural analysis revealed curved multilamellar membrane-like structures in the granular and cornified layers of Fatp4−/− newborn mice (Fig. 1b, inset) that are present in ichthyosis prematurity syndrome patients[25]
Transgenic Fatty acid transport protein 4 (FATP4) or FATP1 expression in mutant suprabasal keratinocytes rescued most of the ultrastructural abnormalities, with partially corrected lamellar body contents (Fig. 1c,d) and normalization of the quantity and structure of lamellar bilayers (Fig. 1g,h)
Summary
Mammalian skin defends against biological, chemical, and mechanical assaults and acts as a barrier to prevent water loss. Several proteins have been implicated in facilitating the uptake of long-chain FAs (LCFA; C12-C20) in mammalian cells[6], including a family of fatty acid www.nature.com/scientificreports/. Www.nature.com/scientificreports transport proteins (FATPs), known as very-long-chain acyl-CoA synthetases[7,8]. The FATP family comprises six membrane proteins that mediate uptake of LCFA and very-long-chain FAs (VLCFA; ≥ C22)[9,10,11,12]. Expression of either a Fatp[4] or a Fatp[1] transgene in suprabasal keratinocytes restores the neonatal lethality and rescues the skin phenotype in Fatp[4] mutants, demonstrating common substrate preferences, enzymatic activities, and biological functions[14,20]
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