The RXR agonists PA024 and HX630 have different abilities to activate LXR/RXR and to induce ABCA1 expression in macrophage cell lines

Tomoko Nishimaki-Mogami, Norimasa Tamehiro, Yoji Sato, Kei ichiro Okuhira, Kimie Sai, Hiroyuki Kagechika, Koichi Shudo, Sumiko Abe-Dohmae, Shinji Yokoyama, Yasuo Ohno, Kazuhide Inoue, Jun ichi Sawada

Research output: Contribution to journalArticle

31 Citations (Scopus)

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 LXRα/RXR transactivation. The ability of HX630 to enhance ABCA1 expression was correlated closely with the cellular PPARγ mRNA level. Moreover, HX630 was able to activate PPARγ/RXR. Transfection of PPARγ in RAW264 cells induced HX630-mediated activation of LXRE-dependent transcription and ABCA1 promoter, suggesting the ability of HX630 to activate PPARγ-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.

Original languageEnglish
Pages (from-to)1006-1013
Number of pages8
JournalBiochemical Pharmacology
Volume76
Issue number8
DOIs
Publication statusPublished - Oct 15 2008
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Pharmacology

Fingerprint Dive into the research topics of 'The RXR agonists PA024 and HX630 have different abilities to activate LXR/RXR and to induce ABCA1 expression in macrophage cell lines'. Together they form a unique fingerprint.

  • Cite this

    Nishimaki-Mogami, T., Tamehiro, N., Sato, Y., Okuhira, K. I., Sai, K., Kagechika, H., Shudo, K., Abe-Dohmae, S., Yokoyama, S., Ohno, Y., Inoue, K., & Sawada, J. I. (2008). The RXR agonists PA024 and HX630 have different abilities to activate LXR/RXR and to induce ABCA1 expression in macrophage cell lines. Biochemical Pharmacology, 76(8), 1006-1013. https://doi.org/10.1016/j.bcp.2008.08.005