Cytochrome P450 eicosanoids are activators of peroxisome proliferator-activated receptor alpha.
Cytochrome P450 (P450) eicosanoids regulate vascular tone, renal tubular transport, cellular proliferation, and inflammation. Both the CYP4A omega-hydroxylases, which catalyze 20-hydroxyeicosatetraenoic acid (20-HETE) formation, and soluble epoxide hydrolase (sEH), which catalyzes epoxyeicosatrienoic acid (EET) degradation to the dihydroxyeicosatrienoic acids (DHETs), are induced upon activation of peroxisome proliferator-activated receptor alpha (PPARalpha) by fatty acids and fibrates. In contrast, the CYP2C epoxygenases, which are responsible for EET formation, are repressed after fibrate treatment. We show here that P450 eicosanoids can bind to and activate PPARalpha and result in the modulation of PPARalpha target gene expression. In transactivation assays, 14,15-DHET, 11,2-EET, and 20-HETE were potent activators of PPARalpha. Gel shift assays showed that EETs, DHETs, and 20-HETE induced PPARalpha-specific binding to its cognate response element. Expression of apolipoprotein A-I was decreased 70% by 20-HETE, whereas apolipoprotein A-II expression was increased up to 3-fold by 11,12-EET, 14,15-DHET, and 20-HETE. In addition, P450 eicosanoids induced CYP4A1, sEH, and CYP2C11 expression, suggesting that they can regulate their own levels. Given that P450 eicosanoids have multiple cardiovascular effects, pharmacological modulation of their formation and/or degradation may yield therapeutic benefits.
Ng
Valerie Y
VY
Department of Biopharmaceutical Sciences, University of California San Francisco, San Francisco, CA 94143-2911, USA.
Huang
Yong
Y
Reddy
L Manmohan
LM
Falck
John R
JR
Lin
Emil T
ET
Kroetz
Deanna L
DL
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism; D016633:Apolipoprotein A-II / Q000235:genetics / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D045744:Cell Line, Tumor; D000090762:Cytochrome P-450 CYP2J2; D042926:Cytochrome P-450 CYP4A / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D000072470:Cytochrome P450 Family 4; D004305:Dose-Response Relationship, Drug; D015777:Eicosanoids / Q000378:metabolism* / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D047493:PPAR alpha / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism; D020025:Peroxisome Proliferators / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020218:Response Elements; D047488:Retinoid X Receptors / Q000378:metabolism; D039181:Steroid 16-alpha-Hydroxylase / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection
C107016:14,15-dihydroxyeicosatrienoic acid; D016632:Apolipoprotein A-I; D016633:Apolipoprotein A-II; C465387:Cyp4a1protein, rat; D015777:Eicosanoids; D006893:Hydroxyeicosatetraenoic Acids; D047493:PPAR alpha; D047495:PPAR gamma; D020025:Peroxisome Proliferators; D011743:Pyrimidines; D012333:RNA, Messenger; D047488:Retinoid X Receptors; C046783:11,12-epoxy-5,8,14-eicosatrienoic acid; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; C006253:pirinixic acid; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D000090762:Cytochrome P-450 CYP2J2; D000072467:Cytochrome P450 Family 2; D000072470:Cytochrome P450 Family 4; D039181:Steroid 16-alpha-Hydroxylase; D042926:Cytochrome P-450 CYP4A; D004851:Epoxide Hydrolases; D015126:8,11,14-Eicosatrienoic Acid