The Epoxygenases CYP2J2 Activates the Nuclear Receptor PPARI- In Vitro and In Vivo

• Published in: PloS one 2009-01, Vol.4 (10), p.e7421-e7421
• Main Authors: Wray, Jessica A, Sugden, Mary C, Zeldin, Darryl C, Greenwood, Gemma K, Samsuddin, Salma, Miller-Degraff, Laura, Bradbury, JAlyce, Holness, Mark J, Warner, Timothy D, Bishop-Bailey, David, TomACO, Daniel
• Format: Article
• Language: English
• ISSN: 1932-6203
• DOI: 10.1371/journal.pone.0007421

Background Peroxisome proliferator-activated receptors (PPARs) are a family of three (PPARI-, -I2/I', and -I3) nuclear receptors. In particular, PPARI- is involved in regulation of fatty acid metabolism, cell growth and inflammation. PPARI- 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 Findings Expression of CYP2J2 in vitro results in an activation of PPAR responses with a particular preference for PPARI-. The CYP2J2 products 8,9- and 11-12-EET also activate PPARI-. In vitro, PPARI- activation by its selective ligand induces the PPARI- 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/Significance Our results establish that CYP2J2 produces PPARI- 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.