Synthesis and degradation pathways, functions, and pathology of ceramides and epidermal acylceramides

Ceramide (Cer) is a structural backbone of sphingolipids and is composed of a long-chain base and a fatty acid. Existence of a variety of Cer species, which differ in chain-length, hydroxylation status, and/or double bond number of either of their hydrophobic chains, has been reported. Ceramide is produced by Cer synthases. Mammals have six Cer synthases (CERS1–6), each of which exhibits characteristic substrate specificity toward acyl-CoAs with different chain-lengths. Knockout mice for each Cer synthase show corresponding, isozyme-specific phenotypes, revealing the functional differences of Cers with different chain-lengths. Cer diversity is especially prominent in epidermis. Changes in Cer levels, composition, and chain-lengths are associated with atopic dermatitis. Acylceramide (acyl-Cer) specifically exists in epidermis and plays an essential role in skin permeability barrier formation. Accordingly, defects in acyl-Cer synthesis cause the cutaneous disorder ichthyosis with accompanying severe skin barrier defects. Although the molecular mechanism by which acyl-Cer is generated was long unclear, most genes involved in its synthesis have been identified recently. In Cer degradation pathways, the long-chain base moiety of Cer is converted to acyl-CoA, which is then incorporated mainly into glycerophospholipids. This pathway generates the lipid mediator sphingosine 1-phosphate. This review will focus on recent advances in our understanding of the synthesis and degradation pathways, physiological functions, and pathology of Cers/acyl-Cers.