The Epoxygenases CYP2J2 Activates the Nuclear Receptor PPARα In Vitro and In Vivo

Jessica A Wray,Salma Samsuddin,Timothy D Warner,Mark J Holness,David Bishop-Bailey,Darryl C Zeldin,Mary C Sugden,Laura Miller-Degraff,J Alyce Bradbury,Gemma K Greenwood,Daniel Tomé

doi:10.1371/journal.pone.0007421

Abstract

BackgroundPeroxisome proliferator-activated receptors (PPARs) are a family of three (PPARα, -β/δ, and -γ) nuclear receptors. In particular, PPARα is involved in regulation of fatty acid metabolism, cell growth and inflammation. PPARα mediates the cardiac fasting response, increasing fatty acid metabolism, decreasing glucose utilisation, and is the target for the fibrate lipid-lowering class of drugs. However, little is known regarding the endogenous generation of PPAR ligands. CYP2J2 is a lipid metabolising cytochrome P450, which produces anti-inflammatory mediators, and is considered the major epoxygenase in the human heart.Methodology/Principal FindingsExpression of CYP2J2 in vitro results in an activation of PPAR responses with a particular preference for PPARα. The CYP2J2 products 8,9- and 11-12-EET also activate PPARα. In vitro, PPARα activation by its selective ligand induces the PPARα target gene pyruvate dehydrogenase kinase (PDK)4 in cardiac tissue. In vivo, in cardiac-specific CYP2J2 transgenic mice, fasting selectively augments the expression of PDK4.Conclusions/SignificanceOur results establish that CYP2J2 produces PPARα ligands in vitro and in vivo, and suggests that lipid metabolising CYPs are prime candidates for the integration of global lipid changes to transcriptional signalling events.

Highlights

Exogenous Peroxisome proliferator-activated receptors (PPARs) activators include a number of fatty acids as well as a variety of eicosanoid, HETEs, HODEs, prostaglandins, and leukotrienes
The combination of CYP2J2 with PPARa (Figure 1A), PPARd or PPARc (Figure 1B) induced a synergistic activation of PPAR reporter genes, with a marked preference in terms of absolute activity for PPARa activation (Figure 1A). pDR-1 was used as a reporter gene for PPARd activation due to the reported lack of efficacy for pACO on PPARd responses [11]
The nature of endogenous PPAR ligands are still far from clear, as is whether PPARs act as general lipid sensors or whether high affinity ligands exist in the body

Summary

Introduction

Exogenous PPAR activators include a number of fatty acids as well as a variety of eicosanoid, HETEs, HODEs, prostaglandins, and leukotrienes. 8,9-, 11,12-, and 14,15-EET and their CYP4A hydroxylase metabolites can bind and activate a PPARa reporter gene [5], and 8,9-, 11,12- and 14,15-EETs can functionally activate both PPARa [6] and PPARc [7,8] in vitro. It is not known which CYPs act as potential sources of the EETs, or whether CYPs or EETs mediate any functional effects on PPARs in vivo. CYP2J2 is a lipid metabolising cytochrome P450, which produces anti-inflammatory mediators, and is considered the major epoxygenase in the human heart

Methods

Results

Conclusion