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

Research output: Contribution to journalArticlepeer-review

21 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 (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.

Original languageEnglish (US)
Pages (from-to)175-184
Number of pages10
JournalProstaglandins and Other Lipid Mediators
Volume82
Issue number1-4
DOIs
StatePublished - Jan 1 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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