LXR促效劑影響U937單核球與巨噬細胞內LXR受器與下游基因表現; Liver X receptor (LXR) agonists affect the expression of LXR and downstream genes in U937 monocyte and macrophage

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Title:	LXR促效劑影響U937單核球與巨噬細胞內LXR受器與下游基因表現;Liver X receptor (LXR) agonists affect the expression of LXR and downstream genes in U937 monocyte and macrophage
Authors:	黃聖翔;Huang,Sheng-xiang
Contributors:	生命科學系
Keywords:	LXR;U937;T0901317;GW3965;ATI-111
Date:	2014-04-17
Issue Date:	2014-06-19 14:00:30 (UTC+8)
Publisher:	國立中央大學
Abstract:	LXR是細胞核受體，它具有調控膽固醇與三酸甘油酯代謝的功能，以及會調節單核球-巨噬細胞系統，所以在動脈硬化中扮演著極重要的角色。本論文使用人類U937單核球與巨噬細胞探討三種LXR促效劑T0901317、GW3965和ATI-111是否會影響LXRα、LXRβ與下游基因的mRNA表現。結果發現T0901317、GW3965和ATI-111在劑量效應與時間效應會增加LXRα和SREBP-1c基因表現，會降低MCP-1和CCL5基因表現，但是不會改變LXRβ、RXRα、resistin和CD11c mRNA表現量。在U937單核球中，T0901317、GW3965和ATI-111影響LXRα的EC50分別為9、15和31 nM，影響SREBP-1c的EC50為3、14和7 nM，影響MCP-1的IC50分別為265、460和149 nM影響CCL5的IC50為1037、472和334 nM。在U937巨噬細胞中，T0901317、GW3965和ATI-111影響LXRα的EC50分別為6、12和0.4 nM，影響SREBP-1c的EC50為0.9、9和5 nM，影響MCP-1的IC50分別為34、80和253 nM，影響CCL5的IC50為69、34和23 nM。因此顯示T0901317、GW3965和ATI-111的生物活性會因細胞發育的狀態、藥物處理的劑量和標的基因而有所不同。此外，細胞在單獨處理葡萄糖時，會增加RXRα、SREBP-1c、MCP-1、CCL5和resistin等基因表現，但會降低LXRα和LXRβ兩種基因的表現。U937細胞在前處理葡萄糖後，結果發現葡萄糖會增強單核球的LXRα基因表現量、降低巨噬細胞的LXRα基因表現量。葡萄糖會降低LXR促效劑對於LXRβ、RXRα、SREBP-1c的效應、加強對於MCP-1和CCL5的效應。這些結果指出這三種LXR促效劑的效果仰賴著營養狀態。LXRα、SREBP-1c、MCP-1和CCL5是調控脂質和發炎功能的基因，這些結果可以解釋LXR促效劑可以調控與發炎有關的疾病。; 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.
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