Effect of Peroxisome Proliferator-Activated Receptor α Activation on Leukotriene B4 Metabolism in Isolated Rat Hepatocytes

  1. Jessica Fiedler1,
  2. Francis R. Simon2,
  3. Mieko Iwahashi2 and
  4. Robert C. Murphy1
  1. 1Division of Cell Biology, National Jewish Medical and Research Center, Denver, Colorado (J.F., R.C.M.); and 2Division of Gastroenterology, University of Colorado Health Sciences Center and Denver Veterans Affairs Medical Center, Denver, Colorado (F.R.S., M.I.)
  1. Dr. Robert C. Murphy, National Jewish Medical and Research Center, 1400 Jackson St., Denver, CO 80206. E-mail: murphyr{at}njc.org

Abstract

Leukotriene B4 (LTB4) is a potent mediator of inflammation that recruits granulocytes to the site of injury during the inflammatory response. The biological activity of LTB4 is terminated by its metabolism into inactive metabolites. Recent studies have suggested that LTB4 may have additional activity as an endogenous ligand for the transcription factor peroxisome proliferator-activated receptor α (PPARα). Based on the data presented, a model was proposed in which LTB4 acts in a negative feedback manner by inducing the transcription of genes involved its own metabolism. In the present study the effect of PPARα activation on LTB4 metabolism was directly investigated. Primary cultures of rat hepatocytes were treated with LTB4 or the PPARα agonist WY-14,643, and LTB4 metabolism was assessed by measuring levels of LTB4 and the formation of LTB4 metabolites. In addition, the effect of PPARα activation on levels of acyl-CoA oxidase mRNA and expression of CYP4F proteins, which are specific ω-hydroxylases for LTB4, was determined. Treatment of hepatocytes with WY-14,643, but not LTB4, was found to increase acyl-CoA oxidase mRNA and enhance expression of rat hepatic CYP4F proteins and CYP4A1. Neither WY-14,643 nor LTB4caused an increase of the basal levels of LTB4 metabolism, and no novel metabolites were observed. These results do not support the hypothesis that a pathway of negative feedback regulation of LTB4 metabolism involving PPARα exists in hepatocytes, because activation of PPARα by LTB4 or other PPARα agonists did not correlate with an increase in LTB4metabolism.

Footnotes

  • This work was supported, in part, by grants from the National Institutes of Health (HL25785, DK15851) and a Veterans Affairs Merit Review (to F.R.S.).

  • Abbreviations:
    LTB4
    leukotriene B4
    (5S,12R)-5,12-dihydroxy-6Z,8E,10E,14Z-eicosatetraenoic acid
    20-OH-LTB4, 20-hydroxy-leukotriene B4, (5S,12R)-5,12,20-trihydroxy-6Z,8E,10E,14Z-eicosatetraenoic acid
    CYP
    cytochrome P450
    20-COOH-LTB4
    20-carboxy-leukotriene B4, (5S,12R)-5,12-dihydroxy-6Z,8E,10E,14Zeicosatetraenoic-1,20-dioic acid
    18-COOH-LTB4
    18-carboxy-dinor-leukotriene B4, (5S,12R)-5,12-dihydroxy-6Z,8E,10E,14Z-octadecatetraene-1,18-dioic acid
    16-COOH-LTB3
    16-carboxy-tetranor-leukotriene B3, (5S,12R)-5,12-dihydroxy-6Z,8E,10E-hexadecatriene-1,16-dioic acid
    PPARα
    peroxisome proliferator-activated receptor α
    WY-14,643
    [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio] acetic acid
    PGB2
    prostaglandin B2
    DMSO
    dimethyl sulfoxide
    MS
    mass spectrometry
    • Received April 18, 2001.
    • Accepted August 9, 2001.
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  1. JPET November 1, 2001 vol. 299 no. 2 691-697
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