Oxidative metabolism of linoleic acid modulates PPAR-beta/delta suppression of PPAR-gamma activity

Oncogene. 2006 Feb 23;25(8):1225-41. doi: 10.1038/sj.onc.1209160.


Peroxisome proliferator-activated receptors (PPARs) are transcription factors that strongly influence molecular events in normal and cancer cells. PPAR-beta/delta (PPAR-b/d) overexpression suppresses the activity of PPAR-gamma (PPAR-g) and PPAR-alpha. This interaction has been questioned, however, by studies with synthetic ligands of PPARs in PPAR-b/d-null cells, and it is not known whether an interaction between PPAR-b/d and PPAR-g exists, especially in relation to the signaling by natural PPAR ligands. Oxidative metabolites of linoleic and arachidonic acids are natural ligands of PPARs. 13-S-hydroxyoctadecadienoic acid (13-S-HODE), the main product of 15-lipoxygenase-1 (15-LOX-1) metabolism of linoleic acid, downregulates PPAR-b/d. We tested (a) whether PPAR-b/d expression modulates PPAR-g activity in experimental models of the loss and gain of PPAR-b/d function in colon cancer cells and (b) whether 15-LOX-1 formation of 13-S-HODE influences the interaction between PPAR-b/d and PPAR-g. We found that (a) 15-LOX-1 formation of 13-S-HODE promoted PPAR-g activity, (b) PPAR-b/d expression suppressed PPAR-g activity in models of both loss and gain of PPAR-b/d function, (c) 15-LOX-1 activated PPAR-g by downregulating PPAR-b/d, and (d) 15-LOX-1 expression induced apoptosis in colon cancer cells via modulating PPAR-b/d suppression of PPAR-g. These findings elucidate a novel mechanism of the signaling by natural ligands of PPARs, which involves modulating the interaction between PPAR-b/d and PPAR-g.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Arachidonate 15-Lipoxygenase / metabolism
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / metabolism
  • Down-Regulation
  • Humans
  • Linoleic Acid / pharmacology*
  • Linoleic Acids / metabolism
  • Oxidation-Reduction
  • PPAR delta / antagonists & inhibitors
  • PPAR delta / metabolism*
  • PPAR gamma / antagonists & inhibitors
  • PPAR gamma / metabolism*
  • PPAR-beta / antagonists & inhibitors
  • PPAR-beta / metabolism*


  • Linoleic Acids
  • PPAR delta
  • PPAR gamma
  • PPAR-beta
  • 13-hydroxy-9,11-octadecadienoic acid
  • Linoleic Acid
  • Arachidonate 15-Lipoxygenase