Epimorphin-derived peptide antagonists remedy epidermal parakeratosis triggered by unsaturated fatty acid.
BACKGROUND
Unsaturated fatty acid from accumulated sebum disrupts calcium influx in keratinocytes and triggers epidermal hyperplasia, leading to comedone formation in the skin. Oleic acid, a representative unsaturated fatty acid, has been shown to be a useful reagent to induce these cellular alternations, however, the detailed mechanism still remains to be elucidated.


OBJECTIVE
This study aimed at the identification of the mediator of unsaturated fatty acid-caused epidermal hyperplasia so as to generate the effective therapeutic agents.


METHODS
The downstream mediator of oleic acid-treatment was identified in the epidermal keratinocyte and the effect of its antagonistic peptides on the epidermal behaviors was investigated in culture and in vivo.


RESULTS
In culture, treatment with oleic acid augmented extracellular secretion of epimorphin in HaCaT keratinocytes and prevented the epidermal terminal differentiation including programmed cell death and cornified envelope formation. The antagonistic peptide of epimorphin (EPn1: a circular compound composed of CGSIEQSC), which was newly generated in this study, restored normal keratinocyte behaviors. In hairless mice, topical application of oleic acid to the dorsal skin caused epidermal hyperplasia with decreased enucleation in the horny layer, which was dramatically hampered by the administration of EPn1.


CONCLUSIONS
The effects of unsaturated fatty acid are attributed to the overstimulation of epimorphin signaling and suggest the epimorphin antagonist as a possible therapeutic agent for acne and hyperkeratotic skin disease.
Okugawa
Yoji
Y
Department of Bioscience, School of Science and Engineering, Kwansei Gakuin University, Sanda 669-1337, Japan.
Bascom
J Jamie
JJ
Hirai
Yohei
Y
D000818:Animals; D017209:Apoptosis; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000187:drug effects; D004817:Epidermis / Q000187:drug effects; D005260:Female; D006801:Humans; D006965:Hyperplasia / Q000188:drug therapy; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008812:Mice, Hairless; D019301:Oleic Acid / Q000009:adverse effects*; D010241:Parakeratosis / Q000139:chemically induced* / Q000188:drug therapy*; D010456:Peptides, Cyclic / Q000494:pharmacology / Q000627:therapeutic use*
C554545:EPn1 peptide; C504582:Epim protein, mouse; D008562:Membrane Glycoproteins; D010456:Peptides, Cyclic; D019301:Oleic Acid