Honokiol increases ABCA1 expression level by activating retinoid X receptor beta.
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 RXRbeta. 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 RXRbeta as a ligand.
Jung
Cha-Gyun
CG
Department of Alzheimer's Disease Research, Research Institute, National Center for Geriatrics and Gerontology, Obu, Aichi 474-8522, Japan. jung@ncgg.go.jp
Horike
Hirofumi
H
Cha
Byung-Yoon
BY
Uhm
Kyung-Ok
KO
Yamauchi
Rena
R
Yamaguchi
Takamasa
T
Hosono
Takashi
T
Iida
Kagami
K
Woo
Je-Tae
JT
Michikawa
Makoto
M
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D001713:Biphenyl Compounds / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D017931:DNA Primers; D006801:Humans; D020287:In Situ Nick-End Labeling; D008024:Ligands; D017705:Lignans / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D049230:Retinoid X Receptor beta / Q000819:agonists*; D000498:Allyl Compounds; D010636:Phenols
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D001713:Biphenyl Compounds; D017931:DNA Primers; D008024:Ligands; D017705:Lignans; D049230:Retinoid X Receptor beta; C577836:ABCA1 protein, human; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols