Honokiol Increases ABCA1 Expression Level by Activating Retinoid X Receptor Beta

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  • Jung Cha-Gyun
    Department of Alzheimer's Disease Research, Research Institute, National Center for Geriatrics and Gerontology (NCGG)
  • Horike Hirofumi
    Department of Alzheimer's Disease Research, Research Institute, National Center for Geriatrics and Gerontology (NCGG)
  • Cha Byung-Yoon
    Research Institute for Biological Functions, Chubu University
  • Uhm Kyung-Ok
    Department of Alzheimer's Disease Research, Research Institute, National Center for Geriatrics and Gerontology (NCGG)
  • Yamauchi Rena
    Department of Alzheimer's Disease Research, Research Institute, National Center for Geriatrics and Gerontology (NCGG)
  • Yamaguchi Takamasa
    Department of Alzheimer's Disease Research, Research Institute, National Center for Geriatrics and Gerontology (NCGG)
  • Hosono Takashi
    Department of Alzheimer's Disease Research, Research Institute, National Center for Geriatrics and Gerontology (NCGG)
  • Iida Kagami
    Research Institute for Biological Functions, Chubu University
  • Woo Je-Tae
    Research Institute for Biological Functions, Chubu University
  • Michikawa Makoto
    Department of Alzheimer's Disease Research, Research Institute, National Center for Geriatrics and Gerontology (NCGG)

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ABCA1, a member of the ATP-binding cassette transporter family, regulates high-density lipoprotein (HDL) metabolism and reverses cholesterol transport. Its expression is upregulated mainly by the activation of the liver X receptor (LXR), retinoid X receptor (RXR), and peroxisome proliferator-activated receptors (PPARs). To identify natural compounds that can upregulate ABCA1 expression, we developed a reporter assay using U251-MG (human glioma cell line) cells that stably express a human ABCA1 promoter-luciferase and performed a cell-based high-throughput screening of 118 natural compounds. Using this system, we identified honokiol, a compound extracted from Magnolia officinalis, as an activator of the ABCA1 promoter. We found that honokiol also increased ABCA1 mRNA and protein expression levels in a dose-dependent manner in U251-MG cells without significant cell death and also increased ABCA1, ABCG1 and apolipoprotein E (apoE) expression levels in THP-1 macrophages. PPAR antagonists did not diminish the induction of ABCA1 expression by honokiol in U251-MG cells. Cotreatment of the cells with honokiol and T0901317 (synthetic LXR ligand) further increased the ABCA1 expression level, whereas cotreatment with 9-cis retinoic acid had no additive effect compared with treatment with honokiol alone. We also found that honokiol has binding affinity to RXRβ. In this study, we identified for the first time honokiol as an upregulator of ABCA1 expression, which is mediated by the binding of honokiol to RXRβ as a ligand.

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