20-carboxy-arachidonic acid is a dual activator of peroxisome proliferator-activated receptors alpha and gamma.
20-carboxy-arachidonic acid (20-COOH-AA) is a metabolite of 20-hydroxyeicosatetraenoic acid (20-HETE), an eicosanoid produced from arachidonic acid by cytochrome P450 (CYP) omega-oxidases. Alcohol dehydrogenases convert 20-HETE to 20-COOH-AA, and we now find that a microsomal preparation containing recombinant human CYP4F3B converts arachidonic acid to 20-HETE and 20-COOH-AA. Studies with transfected COS-7 cell expression systems indicate that 20-COOH-AA activates peroxisome proliferators-activated receptor (PPAR) alpha and PPARgamma. 20-COOH-AA was twice as potent as either 20-HETE or ciglitazone in stimulating PPARgamma-mediated luciferase expression. While 20-COOH-AA also was more potent than 20-HETE in increasing PPARalpha-mediated luciferase expression, the increase was only half as much as that produced by Wy-14643. 20-COOH-AA did not increase PPARalpha or PPARgamma expression in the transfected cells. Radiolabeled 20-COOH-AA was detected intracellularly when the COS-7 cells were incubated with either [3H]20-COOH-AA or [3H]20-HETE, and binding studies indicated that [3H]20-COOH-AA bound to the isolated ligand binding domains of PPARalpha (Kd=0.87+/-0.12 microM) and PPARgamma (Kd=1.7+/-0.5 microM). These findings suggest that 20-COOH-AA, a relatively stable metabolite of 20-HETE, might function as an endogenous dual activator of PPARalpha and PPARgamma.
Fang
Xiang
X
Department of Biochemistry, 4-403 BSB, University of Iowa Carver College of Medicine, Iowa City, IA 52242, United States. xiang-fang@uiowa.edu
Dillon
Joseph S
JS
Hu
Shanming
S
Harmon
Shawn D
SD
Yao
Jianrong
J
Anjaiah
Siddam
S
Falck
J R
JR
Spector
Arthur A
AA
D000818:Animals; D001095:Arachidonic Acids / Q000096:biosynthesis / Q000502:physiology*; D019556:COS Cells; D002522:Chlorocebus aethiops; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D000072470:Cytochrome P450 Family 4; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D051379:Mice; D047493:PPAR alpha / Q000502:physiology*; D047495:PPAR gamma / Q000502:physiology*
D001095:Arachidonic Acids; D006893:Hydroxyeicosatetraenoic Acids; D047493:PPAR alpha; D047495:PPAR gamma; C067517:20-carboxyarachidonic acid; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; D000072470:Cytochrome P450 Family 4; C465349:CYP4F3 protein, human