Document Detail

Oxidative metabolism of linoleic acid modulates PPAR-beta/delta suppression of PPAR-gamma activity.
MedLine Citation:
PMID:  16288226     Owner:  NLM     Status:  MEDLINE    
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.
X Zuo; Y Wu; J S Morris; J B Stimmel; L M Leesnitzer; S M Fischer; S M Lippman; I Shureiqi
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Oncogene     Volume:  25     ISSN:  0950-9232     ISO Abbreviation:  Oncogene     Publication Date:  2006 Feb 
Date Detail:
Created Date:  2006-02-23     Completed Date:  2006-03-28     Revised Date:  2014-09-12    
Medline Journal Info:
Nlm Unique ID:  8711562     Medline TA:  Oncogene     Country:  England    
Other Details:
Languages:  eng     Pagination:  1225-41     Citation Subset:  IM    
Copyright Information:
Oncogene (2006) 25, 1225-1241. doi:10.1038/sj.onc.1209160; published online 14 November 2005.
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MeSH Terms
Adenoviridae / genetics
Arachidonate 15-Lipoxygenase / metabolism
Colorectal Neoplasms / drug therapy*,  metabolism
Linoleic Acid / pharmacology*
Linoleic Acids / metabolism
PPAR delta / antagonists & inhibitors,  metabolism*
PPAR gamma / antagonists & inhibitors,  metabolism*
PPAR-beta / antagonists & inhibitors,  metabolism*
Grant Support
Reg. No./Substance:
0/Linoleic Acids; 0/PPAR delta; 0/PPAR gamma; 0/PPAR-beta; 5204-88-6/13-hydroxy-9,11-octadecadienoic acid; 9KJL21T0QJ/Linoleic Acid; EC 15-Lipoxygenase

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