Open AccessEpidermis-Type Lipoxygenase 3 Regulates Adipocyte Differentiation and Peroxisome Proliferator-Activated Receptor γ Activity
Author(s) -
Philip Hallenborg,
Claus Jørgensen,
Rasmus Koefoed Petersen,
Søren Feddersen,
Pedro Araujo,
Patrick Markt,
Thierry Langer,
Gerhard Fürstenberger,
Peter Krieg,
Arjen Koppen,
Eric Kalkhoven,
Lise Madsen,
Karsten Kristiansen
Publication year - 2010
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.01806-08
Subject(s) - adipogenesis , biology , peroxisome proliferator activated receptor , peroxisome , adipocyte , nuclear receptor , microbiology and biotechnology , cellular differentiation , receptor , gene knockdown , small interfering rna , biochemistry , transcription factor , rna , adipose tissue , mesenchymal stem cell , gene
The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) is essential for adipogenesis. Although several fatty acids and their derivatives are known to bind and activate PPARγ, the nature of the endogenous ligand(s) promoting the early stages of adipocyte differentiation has remained enigmatic. Previously, we showed that lipoxygenase (LOX) activity is involved in activation of PPARγ during the early stages of adipocyte differentiation. Of the seven known murine LOXs, only the unconventional LOX epidermis-type lipoxygenase 3 (eLOX3) is expressed in 3T3-L1 preadipocytes. Here, we show that forced expression of eLOX3 or addition of eLOX3 products stimulated adipogenesis under conditions that normally require an exogenous PPARγ ligand for differentiation. Hepoxilins, a group of oxidized arachidonic acid derivatives produced by eLOX3, bound to and activated PPARγ. Production of hepoxilins was increased transiently during the initial stages of adipogenesis. Furthermore, small interfering RNA-mediated or retroviral short hairpin RNA-mediated knockdown of eLOX3 expression abolished differentiation of 3T3-L1 preadipocytes. Finally, we demonstrate that xanthine oxidoreductase (XOR) and eLOX3 synergistically enhanced PPARγ-mediated transactivation. Collectively, our results indicate that hepoxilins produced by the concerted action of XOR and eLOX3 may function as PPARγ activators capable of promoting the early PPARγ-dependent steps in the conversion of preadipocytes into adipocytes.