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 journalArticle

48 Citations (Scopus)

Abstract

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
Volume366
Issue number3
DOIs
StatePublished - Sep 15 2002
Externally publishedYes

Fingerprint

Lipoxygenase Inhibitors
Peroxisome Proliferator-Activated Receptors
Keratinocytes
Ligands
Lipoxygenase
Keratin-1
Arachidonate Lipoxygenases
Masoprocol
Hydroxyeicosatetraenoic Acids
Differentiation Antigens
Quercetin
Linoleic Acid
Metabolites
Arachidonic Acid
Gene expression
Tumors
Atherosclerosis

Keywords

  • Eicosanoid
  • Flavonoid
  • Nuclear receptor
  • Skin

ASJC Scopus subject areas

  • Biochemistry

Cite this

Inhibition of peroxisome proliferator-activated receptor (PPAR)-mediated keratinocyte differentiation by lipoxygenase inhibitors. / Thuillier, Philippe; Brash, Alan R.; Kehrer, James P.; Stimmel, Julie B.; Leesnitzer, Lisa M.; Yang, Peiying; Newman, Robert A.; Fischer, Susan M.

In: Biochemical Journal, Vol. 366, No. 3, 15.09.2002, p. 901-910.

Research output: Contribution to journalArticle

Thuillier, P, Brash, AR, Kehrer, JP, Stimmel, JB, Leesnitzer, LM, Yang, P, Newman, RA & Fischer, SM 2002, 'Inhibition of peroxisome proliferator-activated receptor (PPAR)-mediated keratinocyte differentiation by lipoxygenase inhibitors', Biochemical Journal, vol. 366, no. 3, pp. 901-910. https://doi.org/10.1042/BJ20020377
Thuillier, Philippe ; Brash, Alan R. ; Kehrer, James P. ; Stimmel, Julie B. ; Leesnitzer, Lisa M. ; Yang, Peiying ; Newman, Robert A. ; Fischer, Susan M. / Inhibition of peroxisome proliferator-activated receptor (PPAR)-mediated keratinocyte differentiation by lipoxygenase inhibitors. In: Biochemical Journal. 2002 ; Vol. 366, No. 3. pp. 901-910.
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