Inhibition of peroxisome proliferator-activated receptor (PPAR)-mediated keratinocyte differentiation by lipoxygenase inhibitors

Philippe Thuillier, Alan R. Brash, James P. Kehrer, Julie B. Stimmel, Lisa M. Leesnitzer, Peiying Yang, Robert A. Newman, Susan M. Fischer

Research output: Contribution to journalArticlepeer-review

58 Scopus citations


Lipoxygenase (LOX) metabolites from arachidonic acid and linoleic acid have been implicated in atherosclerosis, inflammation, keratinocyte differentiation and tumour progression. We previously showed that peroxisome proliferator-activated receptors (PPARs) play a role in keratinocyte differentiation and that the PPARα ligand 8S-hydroxyeicosatetraenoic acid is important in this process. We hypothesized that blocking LOX activity would block PPAR-mediated keratinocyte differentiation. Three LOX inhibitors, nordihydroguaiaretic acid, quercetin and morin, were studied for their effects on primary keratinocyte differentiation and PPAR activity. All three LOX inhibitors blocked calcium-induced expression of the differentiation marker keratin 1. In addition, activity of a PPAR-responsive element was inhibited in the presence of all three inhibitors, and this effect was mediated primarily through PPARα and PPARγ. LOX inhibitors decreased the activity of a chimaeric PPAR-Gal4-ligand-binding domain reporter system and this effect was reversed by addition of PPAR ligands. Ligand-binding studies revealed that the LOX inhibitors bind directly to PPARs and demonstrate a novel mechanism for these inhibitors in altering PPAR-mediated gene expression.

Original languageEnglish (US)
Pages (from-to)901-910
Number of pages10
JournalBiochemical Journal
Issue number3
StatePublished - Sep 15 2002
Externally publishedYes


  • Eicosanoid
  • Flavonoid
  • Nuclear receptor
  • Skin

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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