Cooperative Synthesis of Ultra Long-Chain Fatty Acid and Ceramide during Keratinocyte Differentiation

PLoS One. 2013 Jun 27;8(6):e67317. doi: 10.1371/journal.pone.0067317. Print 2013.


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.

MeSH terms

  • Cell Differentiation / physiology*
  • Ceramides / biosynthesis*
  • Eye Proteins / metabolism
  • Fatty Acids / biosynthesis*
  • Gene Knockdown Techniques
  • HEK293 Cells
  • Humans
  • Immunoblotting
  • In Situ Hybridization
  • Keratinocytes / metabolism*
  • Membrane Proteins / metabolism
  • PPAR delta / genetics
  • PPAR delta / metabolism
  • PPAR-beta / genetics
  • PPAR-beta / metabolism
  • RNA Interference
  • RNA, Messenger / metabolism
  • Real-Time Polymerase Chain Reaction
  • Sphingosine N-Acyltransferase / genetics
  • Sphingosine N-Acyltransferase / metabolism
  • Up-Regulation / physiology


  • Ceramides
  • ELOVL4 protein, human
  • Eye Proteins
  • Fatty Acids
  • Membrane Proteins
  • PPAR delta
  • PPAR-beta
  • RNA, Messenger
  • CERS3 protein, human
  • Sphingosine N-Acyltransferase

Grant support

This work was supported by a Grant-in-Aid for Young Scientists (B) (22770095) from the Ministry of Education, Culture, Sports, Sciences, and Technology of Japan, and in part by grants from the Sapporo Biocluster ‘Bio-S’, the Knowledge Cluster Initiative of the Ministry of Education, Culture, Sports, Science and Technology (MEXT). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.