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Studies on intracellular lipid droplet-associated proteins : Its regulatory mechanism and clinical application

细胞内脂滴相关蛋白的研究：其调控机制及临床应用

基本信息

批准号：
14571099
负责人：
IKUYAMA Shoichiro
金额：
$ 2.24万
依托单位：
Kyushu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14571099/
关键词：
intracellular lipid dronlet ADRP foam cell formation PPAR AP-1 PU.1 マクロファージメチルエステラーゼ

项目摘要

Adipose differentiation-related protein (ADRP) is an intracellular, lipid droplet-associated protein, being expressed ubiquitously including hepatocytes and macrophages, and is involved in intracellular lipid accumulation. Phorbol ester (PMA) stimulated ADRP expression in mouse macrophage RAW264.7 cells. PMA also stimulated ADRP promoter activity in this cell line, and the responsible promoter region was identified between -2090 and -2005bp. When mutations were introduced into the PU.1/AP-1 composite element in this region, the promoter activity decreased. Using gel mobility shift analyses (EMSA), PU.1 as well as AP-1 were shown to bind conjointly bind to this element. On the other hand, PPARγ ligands such as troglitazone stimulated ADRP expression in mouse hepatocyte NMuLi cells. The effect of PPARγ ligands was also mediated by the PU.1/AP-1 element, since mutations in this element decreased the effect. In EMSA complex formation by AR-1 with this element increased when nuclear extracts from troglitazone-treated NMuLi cells were used. A P13 kinase inhibitor, but not inhibitors of MEK and PKC, inhibited troglitazone-induced expression of the ADRP mRNA., thus indicating that PPARγ ligands stimulated AR-1 transcriptional activity through P13 kinase. All these results indicated that the ADRP gene is regulated differently through the same enhancer in the promoter.

脂肪分化相关蛋白（ADRP）是一种细胞内脂滴相关蛋白，广泛表达于肝细胞和巨噬细胞，参与细胞内脂质蓄积。佛波酯（PMA）刺激小鼠巨噬细胞RAW264.7细胞中ADRP的表达。PMA还刺激该细胞系中ADRP启动子的活性，并且在-2090和-2005bp之间鉴定了负责的启动子区域。当在该区域的PU.1/AP-1复合元件中引入突变时，启动子活性降低。使用凝胶迁移率变动分析（EMSA），显示PU. 1以及AP-1共同结合至该元件。另一方面，在小鼠肝细胞NMuLi细胞中，PPARγ配体如曲格列酮刺激ADRP表达。PPARγ配体的作用也由PU.1/AP-1元件介导，因为该元件的突变降低了该作用。在EMSA复合物的形成AR-1与此元素增加时，从曲格列酮处理的NMuLi细胞的核提取物被使用。P13激酶抑制剂，但不是MEK和PKC抑制剂，抑制曲格列酮诱导的ADRP mRNA表达。从而表明PPARγ配体通过P13激酶刺激AR-1转录活性。这些结果表明，ADRP基因通过启动子中的同一增强子进行不同的调控。