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Research ArticleArticle

Activation and Binding of Peroxisome Proliferator-Activated Receptor γ by Synthetic Cannabinoid Ajulemic Acid

Jilin Liu, Hui Li, Sumner H. Burstein, Robert B. Zurier and J. Don Chen
Molecular Pharmacology May 2003, 63 (5) 983-992; DOI: https://doi.org/10.1124/mol.63.5.983
Jilin Liu
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Hui Li
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Sumner H. Burstein
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Robert B. Zurier
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J. Don Chen
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Abstract

Ajulemic acid (AJA) is a synthetic analog of the tetrahydrocannabinol (THC) metabolite THC-11-oic acid; THC is a major active ingredient of the drug marijuana derived from the plant cannabis. AJA has potent analgesic and anti-inflammatory activity without the psychotropic action of THC. Unlike the nonsteroidal anti-inflammatory drugs, AJA is not ulcerogenic at therapeutic doses, making it a promising anti-inflammatory drug. However, the mechanism of AJA action remains unknown. Here we report that AJA binds directly and specifically to the peroxisome proliferator-activated receptor γ (PPARγ), a pharmacologically important member of the nuclear receptor superfamily. Functional assay indicates that AJA activates the transcriptional activity of both human and mouse PPARγ at pharmacological concentrations. Activation of PPARγ by AJA requires the AF-2 helix of the receptor, suggesting that AJA activates PPARγ through the ligand-dependent AF-2 function. AJA binding consistently enables PPARγ to recruit nuclear receptor coactivators. In addition, we show that AJA inhibits interleukin-8 promoter activity in a PPARγ-dependent manner, suggesting a link between the anti-inflammatory action of AJA and the activation of PPARγ. Finally, we find that AJA treatment induces differentiation of 3T3 L1 fibroblasts into adipocytes, a process mediated by PPARγ. Together, these data indicate that PPARγ may be a molecular target for AJA, providing a potential mechanism for the anti-inflammatory action of AJA, and possibly other cannabinoids. These studies also implicate other potential therapeutic actions of AJA through PPARγ activation in multiple signaling pathways.

Footnotes

  • ↵1 Present Address: Department of Pharmacology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey.

  • J.D.C. is a Research Scholar funded by the Leukemia and Lymphoma Society. This work was made possible by grants DK52542 and DK52888 (to J.D.C.), DA09439 and DA09017 (to S.H.B.), and AR38501 (to R.B.Z.) from the National Institutes of Health.

  • Abbreviations:
    THC
    tetrahydrocannabinol
    AJA
    ajulemic acid
    NSAID
    nonsteroidal anti-inflammatory drug
    IL
    interleukin
    PPAR
    peroxisome proliferator-activated receptor
    LBD
    ligand binding domain
    RXR
    retinoid X receptor
    PCR
    polymerase chain reaction
    TK
    thymidine kinase
    PPRE
    peroxisome proliferator-responsive element
    PAGE
    polyacrylamide gel electrophoresis
    GST
    glutathioneS-transferase
    PBS
    phosphate-buffered saline
    HEK
    human embryonic kidney
    DMEM
    Dulbecco's modified Eagle's medium
    PMA
    phorbol 12-myristate 13-acetate
    RT
    reverse transcriptase
    DMSO
    dimethyl sulfoxide
    RA
    retinoic acid
    RAC3
    receptor-associated coactivator-3
    DRIP
    vitamin D receptor interacting protein
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    • Received September 30, 2002.
    • Accepted February 5, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 63 (5)
Molecular Pharmacology
Vol. 63, Issue 5
1 May 2003
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Research ArticleArticle

Activation and Binding of Peroxisome Proliferator-Activated Receptor γ by Synthetic Cannabinoid Ajulemic Acid

Jilin Liu, Hui Li, Sumner H. Burstein, Robert B. Zurier and J. Don Chen
Molecular Pharmacology May 1, 2003, 63 (5) 983-992; DOI: https://doi.org/10.1124/mol.63.5.983

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Research ArticleArticle

Activation and Binding of Peroxisome Proliferator-Activated Receptor γ by Synthetic Cannabinoid Ajulemic Acid

Jilin Liu, Hui Li, Sumner H. Burstein, Robert B. Zurier and J. Don Chen
Molecular Pharmacology May 1, 2003, 63 (5) 983-992; DOI: https://doi.org/10.1124/mol.63.5.983
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