RRC ID 43453
Author Nishimaki-Mogami T, Tamehiro N, Sato Y, Okuhira K, Sai K, Kagechika H, Shudo K, Abe-Dohmae S, Yokoyama S, Ohno Y, Inoue K, Sawada J.
Title The RXR agonists PA024 and HX630 have different abilities to activate LXR/RXR and to induce ABCA1 expression in macrophage cell lines.
Journal Biochem. Pharmacol.
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.
Volume 76(8)
Pages 1006-13
Published 2008-10-15
DOI 10.1016/j.bcp.2008.08.005
PII S0006-2952(08)00534-0
PMID 18761326
MeSH ATP Binding Cassette Transporter 1 ATP Binding Cassette Transporter, Subfamily G, Member 1 ATP-Binding Cassette Transporters / drug effects ATP-Binding Cassette Transporters / genetics* ATP-Binding Cassette Transporters / metabolism ATP-Binding Cassette Transporters / physiology Animals Cell Differentiation / drug effects Cell Line DNA-Binding Proteins / physiology* Humans Liver X Receptors Macrophages / cytology Macrophages / drug effects Macrophages / physiology* Mice Monocytes / drug effects Monocytes / physiology* Orphan Nuclear Receptors PPAR gamma / genetics PPAR gamma / physiology RNA, Messenger / genetics RNA, Ribosomal, 18S / genetics Receptors, Cytoplasmic and Nuclear / physiology* Receptors, Retinoic Acid / agonists Receptors, Retinoic Acid / physiology* Tetradecanoylphorbol Acetate / pharmacology Transfection
IF 4.825
Times Cited 27
Human and Animal Cells