Liver X receptor (LXR) agonists affect the expression of LXR and downstream genes in U937 monocyte and macrophage

• Main Authors: Sheng-xiang Huang, 黃聖翔
• Other Authors: Yung-hsi Kao
• Format: Others
• Language: zh-TW
• Published: 2014
• Online Access: http://ndltd.ncl.edu.tw/handle/28951433760558915841

碩士 === 國立中央大學 === 生命科學系 === 102 === Liver X receptors are nuclear hormone receptors that have been shown to play a major role in atherosclerosis by modulating cholesterol and triglyceride metabolism. Using human U937 monocyte and macrophage, we studied whether the three LXR agonists, such as T0901317, GW3965 and ATI-111, differentially affected mRNA expression of LXRα, LXRβ, and their downstream genes. Generally, these three LXR agonists dose- and time-dependently stimulated LXRα and SREBP-1c mRNA expression and decreased levels of MCP-1 and CCL5 mRNAs, but unaltered levels of LXRβ, RXRα, resistin and CD11c mRNAs. In U937 monocyte, the effective concentrations of T0901317, GW3965 and ATI-111 to increase 50% expression (EC50) were 9, 15 and 31 nM on LXRα gene and 3, 14 and 7 nM on SREBP-1c gene, respectively. The half maximal inhibitory concentrations of T0901317, GW3965 and ATI-111 were 265, 460 and 149 nM on MCP-1 gene and 1037, 472 and 334 nM on CCL-5 gene, respectively. In U937 macrophage, the EC50s of T0901317, GW3965 and ATI-111 to increase expression were 6, 12 and 0.4 nM on LXRα and 0.9, 9 and 5 nM on SREBP-1c gene, respectively. The half maximal inhibitory concentrations of T0901317, GW3965 and ATI-111 were 34, 80 and 253 nM on MCP-1 gene and 69, 34 and 23 nM on CCL-5 gene, respectively. These data suggest that the biological potencies of these three LXR agonists vary with the development status, the dose of treatment, and target genes. Further study showed that glucose alone increased levels of RXRα, SREBP-1c, MCP-1, CCL5 and resistin mRNAs and decreased levels of LXRα and LXRβ mRNAs. Increases in the level of LXRα mRNA expressioin stimulated by LXR agonist would be enhanced in monocyte and decreased in macrophage by glucose pretreatment. However, glucose reduced the LXR agonist-induced increases in levels of LXRβ, RXRα, SREBP-1c, MCP-1 and CCL5 mRNAs. These data indicate the nutritional status-dependent effect of these three LXR agonists. As LXRα, SREBP-1c, MCP-1 and CCL-5 have been respectively reported to regulate lipid metabolism and inflammation, results of the study may help explain the effect of these three LXR agonists on inflammation-related disease.