Abstract
The lipid lamellae in the stratum corneum is important for the epidermal permeability barrier. The lipid lamellae component ceramide (CER), comprising an ultra long-chain (ULC) fatty acid (FA) of ≥26 carbons (ULC CER), plays an essential role in barrier formation. ULC acyl-CoAs, produced by the FA elongase ELOVL4, are converted to ULC CERs by the CER synthase CERS3. In the presented study, we observed that ELOVL4 and CERS3 mRNAs increased during keratinocyte differentiation in vivo and in vitro. We also determined that peroxisome proliferator-activated receptor β/δ is involved in the up-regulation of the mRNAs. Knockdown of CERS3 caused a reduction in the elongase activities toward ULC acyl-CoAs, suggesting that CERS3 positively regulates ULCFA. Thus, we reveal that the two key players in ULC CER production in epidermis, CERS3 and ELOVL4, are coordinately regulated at both the transcriptional and enzymatic levels.
Highlights
The outermost layers of the epidermis are responsible for critical protective functions, including permeability barrier functions against water loss [1,2]
We speculated that CERS3 plays important functions in the synthesis of very long-chain (VLC) CERs/ultra long-chain (ULC) CERs, and in the regulation of VLCFA/ULCFA production, in differentiated keratinocytes
The prominent up-regulation of the ELOVL4 mRNA may be responsible for the production of substantial levels of ULCFAs required for cutaneous barrier functions
Summary
The outermost layers of the epidermis are responsible for critical protective functions, including permeability barrier functions against water loss [1,2]. The epidermal permeability barrier is localized in the extracellular domains of the stratum corneum (SC), where a hydrophobic lipid mixture is organized into distinct multi-lamellar membrane structures composed primarily of free fatty acids (FAs), cholesterol, and ceramides (CERs) [3,4]. The balance of these lipids in SC is, in general, important for skin functions, and their production should be commonly regulated. Both can be converted back to their CER species, via hydrolysis occurring at a site lying between the SG and SC, CER is incorporated into the lipid lamellae in the SC [3]
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