Farnesyl phosphates are endogenous ligands of lysophosphatidic acid receptors: Inhibition of LPA GPCR and activation of PPARs

K. Liliom, Tamotsu Tsukahara, Ryoko Tsukahara, Monika Zelman-Femiak, Ewa Swiezewska, Gabor Tigyi

Research output: Contribution to journalArticle

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Abstract

Oligoprenyl phosphates are key metabolic intermediates for the biosynthesis of steroids, the side chain of ubiquinones, and dolichols and the posttranslational isoprenylation of proteins. Farnesyl phosphates are isoprenoid phosphates that resemble polyunsaturated fatty alcohol phosphates, which we have recently shown to be the minimal pharmacophores of lysophosphatidic acid (LPA) receptors. Here we examine whether farnesyl phosphates can interact with the cell surface and nuclear receptors for LPA. Both farnesyl phosphate and farnesyl diphosphate potently and specifically antagonized LPA-elicited intracellular Ca2+-mobilization mediated through the LPA3 receptor, while causing only modest inhibition at the LPA2 receptor and no measurable effect at the LPA1 receptor. Farnesol also inhibited LPA3 but was much less effective. The estimated dissociation constant of LPA3 for farnesyl phosphate is 48 ± 12 nM and 155 ± 30 nM for farnesyl diphosphate. The transcription factor peroxisome proliferator-activated receptor gamma (PPARγ) binds to and is activated by LPA and its analogs including fatty alcohol phosphates. We found that both farnesyl phosphate and diphosphate, but not farnesol, compete with the binding of the synthetic PPARγ agonist [3H]rosiglitazone and activate the PPARγ-mediated gene transcription. Farnesyl monophosphate at 1 μM, but not diphosphate, activated PPARα and PPARβ/δ reporter gene expression. These results indicate new potential roles for the oligoprenyl phosphates as potential endogenous modulators of LPA targets and show that the polyisoprenoid chain is recognized by some LPA receptors.

Original languageEnglish
Pages (from-to)1506-1514
Number of pages9
JournalBiochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Volume1761
Issue number12
DOIs
Publication statusPublished - Dec 2006

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Lysophosphatidic Acid Receptors
Peroxisome Proliferator-Activated Receptors
Phosphates
Ligands
PPAR gamma
Farnesol
Fatty Alcohols
rosiglitazone
Polyisoprenyl Phosphates
Protein Prenylation
Dolichol
lysophosphatidic acid
Ubiquinone
Diphosphates
Cell Surface Receptors
Cytoplasmic and Nuclear Receptors
Reporter Genes
Transcription Factors
Steroids

Keywords

  • Farnesyl phosphate
  • GPCR
  • Isoprenoid
  • LPA
  • Lysophospholipid
  • PPARγ

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Biophysics

Cite this

Farnesyl phosphates are endogenous ligands of lysophosphatidic acid receptors : Inhibition of LPA GPCR and activation of PPARs. / Liliom, K.; Tsukahara, Tamotsu; Tsukahara, Ryoko; Zelman-Femiak, Monika; Swiezewska, Ewa; Tigyi, Gabor.

In: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, Vol. 1761, No. 12, 12.2006, p. 1506-1514.

Research output: Contribution to journalArticle

Liliom, K. ; Tsukahara, Tamotsu ; Tsukahara, Ryoko ; Zelman-Femiak, Monika ; Swiezewska, Ewa ; Tigyi, Gabor. / Farnesyl phosphates are endogenous ligands of lysophosphatidic acid receptors : Inhibition of LPA GPCR and activation of PPARs. In: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. 2006 ; Vol. 1761, No. 12. pp. 1506-1514.
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AU - Zelman-Femiak, Monika

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AU - Tigyi, Gabor

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