👤 Norimasa Tamehiro

Liver X receptors (LXRα and LXRβ) are nuclear receptors critical for lipid homeostasis and inflammation regulation, making them potential therapeutic targets for atherosclerosis and inflammatory diseases. While LXR agonists hold promise, their use is limited by adverse effects on hepatic lipogenesis. Riccardin C (RC) has shown promise as an LXRα partial agonist/ LXRβ antagonist with cell-type-selective properties. This study investigates the molecular mechanisms behind RC-induced LXRα activation. A series of LXRα/β chimera and point-mutated receptors was generated to identify the domains and residues required for RC-induced transactivation. Functional analysis revealed that mutating alanine-327 of LXRα to LXRβ-type histidine in helix 6 impaired RC-induced association with coactivator peptides, reducing transactivation. Conversely, mutating histidine-341 of LXRβ or the inactive chimera to the LXRα-type alanine partially restored the response to RC, highlighting the significance of the A327H mutation in selective LXRα activation by RC. Furthermore, in vivo experiments revealed that when administered orally to mice, RC selectively induced hepatic and intestinal Abca1 expression without stimulating hepatic lipogenic gene expression, thereby elevating HDL levels without increasing plasma and hepatic triglycerides. These findings offer valuable insights for the development of novel therapeutic agents. Show less

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. Show less