title: The RXR agonists PA024 and HX630 have different abilities to activate LXR/RXR and to induce ABCA1 expression in macrophage cell lines.
abstract: Release of cellular cholesterol by ATP-binding cassette transporter (ABC)A1 and apolipoproteins is a major source of plasma high-density lipoprotein (HDL). Expression of ABC transporter A1 (ABCA1) is directly stimulated by liver X receptor (LXR)/retinoid X receptor (RXR) activation. We evaluated the abilities of two RXR agonists, PA024 and HX630, to increase ABCA1 expression. In differentiated THP-1 cells, the two agonists efficiently enhanced ABCA1 mRNA expression and apoA-I-dependent cellular cholesterol release. However, in RAW264 cells and undifferentiated THP-1 cells, PA024 was highly effective while HX630 was inactive in increasing ABCA1 mRNA. In parallel, the two agonists had different abilities to activate ABCA1 promoter in an LXR-responsive-element (LXRE)-dependent manner and to directly stimulate LXRalpha/RXR transactivation. The ability of HX630 to enhance ABCA1 expression was correlated closely with the cellular PPARgamma mRNA level. Moreover, HX630 was able to activate PPARgamma/RXR. Transfection of PPARgamma in RAW264 cells induced HX630-mediated activation of LXRE-dependent transcription and ABCA1 promoter, suggesting the ability of HX630 to activate PPARgamma-LXR-ABCA1 pathway. We conclude that RXR agonist PA024 and HX630 have different abilities to activate LXR/RXR, and that the cell-type-dependent effect of HX630 on ABCA1 expression and HDL generation is closely associated with this defect.
authors.affiliation: Division of Biosignaling, National Institute of Health Sciences, Tokyo, Japan. mogami@nihs.go.jp
authors.forename: Tomoko
authors.initials: T
authors.lastname: Nishimaki-Mogami
authors.forename: Norimasa
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authors.lastname: Tamehiro
authors.forename: Yoji
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authors.lastname: Sato
authors.forename: Kei-ichiro
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authors.lastname: Okuhira
authors.forename: Kimie
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authors.lastname: Sai
authors.forename: Hiroyuki
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authors.lastname: Kagechika
authors.forename: Koichi
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authors.lastname: Shudo
authors.forename: Sumiko
authors.initials: S
authors.lastname: Abe-Dohmae
authors.forename: Shinji
authors.initials: S
authors.lastname: Yokoyama
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ohno
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Inoue
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Sawada