The epoxygenases CYP2J2 activates the nuclear receptor PPARalpha in vitro and in vivo.
BACKGROUND
Peroxisome proliferator-activated receptors (PPARs) are a family of three (PPARalpha, -beta/delta, and -gamma) nuclear receptors. In particular, PPARalpha is involved in regulation of fatty acid metabolism, cell growth and inflammation. PPARalpha 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.


RESULTS
Expression of CYP2J2 in vitro results in an activation of PPAR responses with a particular preference for PPARalpha. The CYP2J2 products 8,9- and 11-12-EET also activate PPARalpha. In vitro, PPARalpha activation by its selective ligand induces the PPARalpha 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
Our results establish that CYP2J2 produces PPARalpha 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.
Wray
Jessica A
JA
Translational Medicine and Therapeutics, William Harvey Research Institute, London, United Kingdom.
Sugden
Mary C
MC
Zeldin
Darryl C
DC
Greenwood
Gemma K
GK
Samsuddin
Salma
S
Miller-Degraff
Laura
L
Bradbury
J Alyce
JA
Holness
Mark J
MJ
Warner
Timothy D
TD
Bishop-Bailey
David
D
D000818:Animals; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation; D008024:Ligands; D008055:Lipids / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D047493:PPAR alpha / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D014158:Transcription, Genetic
C000717350:CYP2J2 protein, human; D008024:Ligands; D008055:Lipids; D047493:PPAR alpha; D003577:Cytochrome P-450 Enzyme System; D000090762:Cytochrome P-450 CYP2J2; D011494:Protein Kinases; C403287:pyruvate dehydrogenase kinase 4