title: Stimulation of PPARα normalizes the skin lipid ratio and improves the skin barrier of normal and filaggrin deficient reconstructed skin.
abstract: BACKGROUND
  Therapeutic options for atopic dermatitis mostly address the symptoms but causal therapies are still missing. Peroxisome proliferator activated receptor (PPAR) agonists exert beneficial effects in patients suffering this disease, whereas the stimulation of PPARα and γ seemed most promising.
  
  
  OBJECTIVE
  To elucidate the effects of the PPARα specific agonist WY14643, the PPARγ agonist ciglitazone, and the dual PPARα+γ agonist docosahexaenoic acid (DHA) on the homeostasis and barrier function of filaggrin deficient skin.
  
  
  METHODS
  The effects of the PPAR agonists on skin differentiation were evaluated via qPCR, Western blot, histological or immunofluorescence staining. Skin lipid organization was determined by ATR-FTIR and lipid composition was analyzed by HPTLC. Ultimately, the skin barrier function was assessed by skin absorption studies using the radioactively labeled compound testosterone.
  
  
  RESULTS
  Significant upregulation of filaggrin after DHA and WY14643 supplementation, but no effect of ciglitazone, on protein and mRNA level was detected. DHA and WY14643, but not ciglitazone, normalized the molar ratio of the main skin barrier lipids to 1:1:1 (free fatty acids:ceramides:cholesterol). Furthermore, DHA and WY14643 supplementation normalized the skin lipid profile in filaggrin deficient skin, but only WY14643 significantly improved the skin barrier function.
  
  
  CONCLUSIONS
  Supplementation particularly with the PPARα agonist WY14643 improved the homeostasis and barrier function of filaggrin deficient skin models by normalization of the free fatty acid profile underlining the potential of PPAR agonists for the treatment of filaggrin-associated skin diseases.
authors.affiliation: Institute for Pharmaceutical Sciences, Pharmacology and Toxicology, Freie Universität Berlin, Germany.
authors.forename: Leonie
authors.initials: L
authors.lastname: Wallmeyer
authors.affiliation: Institute for Pharmaceutical Sciences, Pharmacology and Toxicology, Freie Universität Berlin, Germany.
authors.forename: Dominika
authors.initials: D
authors.lastname: Lehnen
authors.affiliation: Institute for Pharmaceutical Sciences, Pharmacology and Toxicology, Freie Universität Berlin, Germany.
authors.forename: Natascha
authors.initials: N
authors.lastname: Eger
authors.affiliation: Charles University Prague, Faculty of Pharmacy, Hradec Kralove, Czech Republic.
authors.forename: Michaela
authors.initials: M
authors.lastname: Sochorová
authors.affiliation: Charles University Prague, Faculty of Pharmacy, Hradec Kralove, Czech Republic.
authors.forename: Lukáš
authors.initials: L
authors.lastname: Opálka
authors.affiliation: Charles University Prague, Faculty of Pharmacy, Hradec Kralove, Czech Republic.
authors.forename: Andrej
authors.initials: A
authors.lastname: Kováčik
authors.affiliation: Charles University Prague, Faculty of Pharmacy, Hradec Kralove, Czech Republic.
authors.forename: Kateřina
authors.initials: K
authors.lastname: Vávrová
authors.affiliation: Institute for Pharmaceutical Sciences, Pharmacology and Toxicology, Freie Universität Berlin, Germany. Electronic address: sarah.hedtrich@fu-berlin.de.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hedtrich
mesh_terms: D002478:Cells, Cultured; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D000091344:Filaggrin Proteins; D005838:Genotype; D006801:Humans; D007381:Intermediate Filament Proteins / Q000172:deficiency* / Q000235:genetics; D050356:Lipid Metabolism / Q000187:drug effects*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D010539:Permeability; D010641:Phenotype; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000187:drug effects* / Q000378:metabolism; D012869:Skin Absorption / Q000187:drug effects*; D013739:Testosterone / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection
chemical_list: C000717249:FLG protein, human; D005230:Fatty Acids, Nonesterified; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D008565:Membrane Proteins; D047493:PPAR alpha; D047495:PPAR gamma; D011498:Protein Precursors; D011743:Pyrimidines; D045162:Thiazolidinediones; C064554:loricrin; D004281:Docosahexaenoic Acids; D013739:Testosterone; C032253:involucrin; C006253:pirinixic acid; C039671:ciglitazone
keywords: Filaggrin deficiency; PPAR agonists; Reconstructed skin models; Skin barrier recovery; Skin lipids