20-Carboxy-arachidonic acid is a dual activator of peroxisome proliferator-activated receptors α and γ

Xiang Fang; Joseph S. Dillon; Shanming Hu; Shawn D. Harmon; Jianrong Yao; Siddam Anjaiah; J R Falck; Arthur A. Spector

doi:10.1016/j.prostaglandins.2006.05.002

20-Carboxy-arachidonic acid is a dual activator of peroxisome proliferator-activated receptors α and γ

Xiang Fang, Joseph S. Dillon, Shanming Hu, Shawn D. Harmon, Jianrong Yao, Siddam Anjaiah, J R Falck, Arthur A. Spector

Biochemistry

Research output: Contribution to journal › Article › peer-review

31 Scopus citations

Abstract

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) ω-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) α and PPARγ. 20-COOH-AA was twice as potent as either 20-HETE or ciglitazone in stimulating PPARγ-mediated luciferase expression. While 20-COOH-AA also was more potent than 20-HETE in increasing PPARα-mediated luciferase expression, the increase was only half as much as that produced by Wy-14643. 20-COOH-AA did not increase PPARα or PPARγ 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 PPARα (K_d = 0.87 ± 0.12 μM) and PPARγ (K_d = 1.7 ± 0.5 μM). These findings suggest that 20-COOH-AA, a relatively stable metabolite of 20-HETE, might function as an endogenous dual activator of PPARα and PPARγ.

Original language	English (US)
Pages (from-to)	175-184
Number of pages	10
Journal	Prostaglandins and Other Lipid Mediators
Volume	82
Issue number	1-4
DOIs	https://doi.org/10.1016/j.prostaglandins.2006.05.002
State	Published - Jan 2007

Keywords

20-HETE
Arachidonic acid
Cytochrome P450
Nuclear receptors
ω-Oxidation

ASJC Scopus subject areas

Biochemistry
Physiology
Pharmacology
Cell Biology

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10.1016/j.prostaglandins.2006.05.002

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@article{fb3b107409054b65b360bf9a24a558ca,

title = "20-Carboxy-arachidonic acid is a dual activator of peroxisome proliferator-activated receptors α and γ",

abstract = "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) ω-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) α and PPARγ. 20-COOH-AA was twice as potent as either 20-HETE or ciglitazone in stimulating PPARγ-mediated luciferase expression. While 20-COOH-AA also was more potent than 20-HETE in increasing PPARα-mediated luciferase expression, the increase was only half as much as that produced by Wy-14643. 20-COOH-AA did not increase PPARα or PPARγ 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 PPARα (Kd = 0.87 ± 0.12 μM) and PPARγ (Kd = 1.7 ± 0.5 μM). These findings suggest that 20-COOH-AA, a relatively stable metabolite of 20-HETE, might function as an endogenous dual activator of PPARα and PPARγ.",

keywords = "20-HETE, Arachidonic acid, Cytochrome P450, Nuclear receptors, ω-Oxidation",

author = "Xiang Fang and Dillon, {Joseph S.} and Shanming Hu and Harmon, {Shawn D.} and Jianrong Yao and Siddam Anjaiah and Falck, {J R} and Spector, {Arthur A.}",

note = "Funding Information: We thank Dr. Ronald M. Evans (Salk Institute, Howard Hughes Medical Institute) for providing the PPAR plasmids; and Dr. John Shyy (University of California, Riverside) for providing the GST-mPPARα-LBD and GST-mPPARγ-LBD proteins. This study was supported in part by American Heart Association Scientist Development Grant 0230096N (to XF), National Institutes of Health grants HL072845 (to AAS), DK038226 and GM31278, and the Robert A. Welch Foundation (to JRF).",

year = "2007",

month = jan,

doi = "10.1016/j.prostaglandins.2006.05.002",

language = "English (US)",

volume = "82",

pages = "175--184",

journal = "Prostaglandins and Other Lipid Mediators",

issn = "1098-8823",

publisher = "Elsevier BV",

number = "1-4",

}

TY - JOUR

T1 - 20-Carboxy-arachidonic acid is a dual activator of peroxisome proliferator-activated receptors α and γ

AU - Fang, Xiang

AU - Dillon, Joseph S.

AU - Hu, Shanming

AU - Harmon, Shawn D.

AU - Yao, Jianrong

AU - Anjaiah, Siddam

AU - Falck, J R

AU - Spector, Arthur A.

N1 - Funding Information: We thank Dr. Ronald M. Evans (Salk Institute, Howard Hughes Medical Institute) for providing the PPAR plasmids; and Dr. John Shyy (University of California, Riverside) for providing the GST-mPPARα-LBD and GST-mPPARγ-LBD proteins. This study was supported in part by American Heart Association Scientist Development Grant 0230096N (to XF), National Institutes of Health grants HL072845 (to AAS), DK038226 and GM31278, and the Robert A. Welch Foundation (to JRF).

PY - 2007/1

Y1 - 2007/1

N2 - 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) ω-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) α and PPARγ. 20-COOH-AA was twice as potent as either 20-HETE or ciglitazone in stimulating PPARγ-mediated luciferase expression. While 20-COOH-AA also was more potent than 20-HETE in increasing PPARα-mediated luciferase expression, the increase was only half as much as that produced by Wy-14643. 20-COOH-AA did not increase PPARα or PPARγ 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 PPARα (Kd = 0.87 ± 0.12 μM) and PPARγ (Kd = 1.7 ± 0.5 μM). These findings suggest that 20-COOH-AA, a relatively stable metabolite of 20-HETE, might function as an endogenous dual activator of PPARα and PPARγ.

AB - 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) ω-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) α and PPARγ. 20-COOH-AA was twice as potent as either 20-HETE or ciglitazone in stimulating PPARγ-mediated luciferase expression. While 20-COOH-AA also was more potent than 20-HETE in increasing PPARα-mediated luciferase expression, the increase was only half as much as that produced by Wy-14643. 20-COOH-AA did not increase PPARα or PPARγ 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 PPARα (Kd = 0.87 ± 0.12 μM) and PPARγ (Kd = 1.7 ± 0.5 μM). These findings suggest that 20-COOH-AA, a relatively stable metabolite of 20-HETE, might function as an endogenous dual activator of PPARα and PPARγ.

KW - 20-HETE

KW - Arachidonic acid

KW - Cytochrome P450

KW - Nuclear receptors

KW - ω-Oxidation

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U2 - 10.1016/j.prostaglandins.2006.05.002

DO - 10.1016/j.prostaglandins.2006.05.002

M3 - Article

C2 - 17164145

AN - SCOPUS:33845344737

SN - 1098-8823

VL - 82

SP - 175

EP - 184

JO - Prostaglandins and Other Lipid Mediators

JF - Prostaglandins and Other Lipid Mediators

IS - 1-4

ER -

20-Carboxy-arachidonic acid is a dual activator of peroxisome proliferator-activated receptors α and γ

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Keywords

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