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

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...

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Bibliographic Details
Published in:Biochemical journal 2002-09, Vol.366 (Pt 3), p.901-910
Main Authors: Thuillier, Philippe, Brash, Alan R, Kehrer, James P, Stimmel, Julie B, Leesnitzer, Lisa M, Yang, Peiying, Newman, Robert A, Fischer, Susan M
Format: Article
Language:English
Subjects:
Animals
Arachidonic Acid - metabolism
Blotting, Northern
Blotting, Western
Cell Differentiation
Cell Survival
Cells, Cultured
Dose-Response Relationship, Drug
Enzyme Inhibitors - pharmacology
Genes, Reporter
Inhibitory Concentration 50
Keratinocytes - metabolism
Keratins - metabolism
Ligands
Linoleic Acid - metabolism
Lipoxygenase - metabolism
Mice
Protein Binding
Receptors, Cytoplasmic and Nuclear - metabolism
Time Factors
Transcription Factors - metabolism
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Summary: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.
ISSN:0264-6021
1470-8728
DOI:10.1042/BJ20020377