title: Decreases in 15-lipoxygenase metabolites in Olmsted syndrome model rats.
abstract: BACKGROUND
  Olmsted syndrome (OS) is a congenital dermatosis characterized by palmoplantar keratoderma and periorificial keratotic plaque. TRPV3 (transient receptor potential vanilloid subtype 3) encodes a thermosensitive Ca2+channel and is the causative gene of OS. However, the molecular mechanism that causes the pathological development of OS is unclear.
  
  
  OBJECTIVE
  We aimed to investigate the molecular mechanisms underlying OS pathology from the perspective of lipid metabolism.
  
  
  METHODS
  Comprehensive lipidomics and microarray analyses were conducted on tissue samples from a non-lesional skin area of OS model rats (Ht rats) and from wild type (WT) rats as the control.
  
  
  RESULTS
  Infiltration of leukocytes such as eosinophils and neutrophils and an increase in the fibrotic region were detected in the unaffected skin area of Ht rats compared with the WT rats. Among about 600 lipid species examined, the levels of 15-lipoxygenase (LOX) metabolites, the precursors of anti-inflammatory and pro-resolving lipid mediators, and dihydroceramides decreased by ≥16-fold in Ht rats compared with WT rats. Consistent with the decreases in the 15-LOX metabolites, expression levels of the genes that encode the 15-LOXs, Alox15 and Alox15b, were largely reduced. Conversely, increased expression levels were detected of Il36b, Ccl20, Cxcl1, and Cxcl2, which encode cytokines/chemokines, and S100a8 and S100a9, which encode the Ca2+binding proteins that are implicated in epidermal proliferation.
  
  
  CONCLUSIONS
  The pro-inflammatory state in the unaffected skin of Ht rats caused by decreases in 15-LOX metabolites and increases in cytokines/chemokines may contribute to the pathogenesis of OS.
authors.affiliation: Shionogi Innovation Center for Drug Discovery, Discovery Research Laboratory for Innovative Frontier Medicines, Shionogi & Co., Ltd., Sapporo 001-0021, Japan; Laboratory of Biochemistry, Graduate School of Life Science, Hokkaido University, Sapporo 060-0812, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Wakabayashi
authors.affiliation: Shionogi Innovation Center for Drug Discovery, Discovery Research Laboratory for Innovative Frontier Medicines, Shionogi & Co., Ltd., Sapporo 001-0021, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yoshioka
authors.affiliation: Shionogi Innovation Center for Drug Discovery, Discovery Research Laboratory for Innovative Frontier Medicines, Shionogi & Co., Ltd., Sapporo 001-0021, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Higashino
authors.affiliation: Shionogi Innovation Center for Drug Discovery, Discovery Research Laboratory for Innovative Frontier Medicines, Shionogi & Co., Ltd., Sapporo 001-0021, Japan.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Numata
authors.affiliation: Laboratory of Biomembrane and Biofunctional Chemistry, Faculty of Advanced Life Science, Hokkaido University, Sapporo 001-0021, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Igarashi
authors.affiliation: Laboratory of Biochemistry, Graduate School of Life Science, Hokkaido University, Sapporo 060-0812, Japan; Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan. Electronic address: kihara@pharm.hokudai.ac.jp.
authors.forename: Akio
authors.initials: A
authors.lastname: Kihara
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism*; D040501:Calgranulin A / Q000378:metabolism; D040502:Calgranulin B / Q000378:metabolism; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D007645:Keratoderma, Palmoplantar / Q000235:genetics / Q000378:metabolism*; D007962:Leukocytes; D050356:Lipid Metabolism / Q000235:genetics*; D008854:Microscopy, Electron; D051381:Rats; D013577:Syndrome; D050916:TRPV Cation Channels / Q000235:genetics
chemical_list: D040501:Calgranulin A; D040502:Calgranulin B; D016207:Cytokines; D050916:TRPV Cation Channels; C505767:TRPV3 protein, rat; D001093:Arachidonate 15-Lipoxygenase
keywords: 15-Lipoxygenase; Lipid; Lipidomics; Olmsted syndrome; TRPV3