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.
Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12-jo, Nishi 6-choume, Kita-ku, Sapporo 060-0812, Japan. Electronic address: kihara@pharm.hokudai.ac.jp.
Akio
A
Kihara
D000123:Acetyltransferases / Q000378:metabolism; D000429:Alcohol Oxidoreductases / Q000378:metabolism; D000818:Animals; D002518:Ceramides / Q000737:chemistry / Q000378:metabolism*; D003876:Dermatitis, Atopic / Q000378:metabolism / Q000473:pathology; D004817:Epidermis / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D006801:Humans; D051102:Serine C-Palmitoyltransferase / Q000378:metabolism; D051049:Sphingosine N-Acyltransferase / Q000378:metabolism; D013379:Substrate Specificity
D002518:Ceramides; D005227:Fatty Acids; D000429:Alcohol Oxidoreductases; C023943:3-ketodihydrosphingosine reductase; D000123:Acetyltransferases; D051049:Sphingosine N-Acyltransferase; D051102:Serine C-Palmitoyltransferase
Acylceramide; Ceramide; Fatty acid; Long-chain base; Skin barrier; Sphingolipid