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

Thuillier P, Brash AR, Kehrer JP, Stimmel JB, Leesnitzer LM, Yang P, Newman RA, Fischer SM
Biochem J. 2002 366 (Pt 3): 901-10

PMID: 12069687 · PMCID: PMC1222830 · DOI:10.1042/BJ20020377

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 PPARalpha 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 PPARalpha and PPARgamma. 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.

MeSH Terms (21)

Animals Arachidonic Acid Blotting, Northern Blotting, Western Cell Differentiation Cells, Cultured Cell Survival Dose-Response Relationship, Drug Enzyme Inhibitors Genes, Reporter Inhibitory Concentration 50 Keratinocytes Keratins Ligands Linoleic Acid Lipoxygenase Mice Protein Binding Receptors, Cytoplasmic and Nuclear Time Factors Transcription Factors

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