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Transcription factoys in autoimmune thiroid disease : its relevance to pathophysiology and novel therapeutic strategy

自身免疫性甲状腺疾病的转录因子：其与病理生理学和新治疗策略的相关性

基本信息

批准号：
10671038
负责人：
IKUYAMA Shoichiro
金额：
$ 2.11万
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：
1998
资助国家：
日本
起止时间：
1998 至 2000
项目状态：
已结题

项目摘要

In order to search new therapeutic strategies for autoimmune thyroid diseases, we have worked on adipose differentiation-related protein (ADRP), which was originally identified as an early marker of adipose cell differentiation program. This protein is ubiquitously expressed and is involved in lipid storage as well as long chain fatty acid uptake. Since free fatty acid could be a mediator of inflammatory response, we aimed to disclose the regulatory mechanism of the ADRP gene expression. In the present study, we disclosed that the mouse ADRP gene expression is regulated by PPARg. Thus, PPARg ligands, troglitazone, pioglitazone and 1 5 -deoxy-D12,14-prostaglandin J2, increased ADRP mRNA levels in NMuLi mouse liver cells and J774.1 mouse macrophages in vitro. This increase was completely inhibited by actinomycin D.On the contrary, PPARa ligands, fenofibrate and bezafibrate, failed to increase the mRNA levels. In order to delineate the promoter region responsible for this PPARg-induced stimulation, we cloned an approximately 2.8kb 5'-flanking region of the mouse ADRP gene, and constructed luciferase reporter plasmids for the assessment of promoter activity. All chimeric constructs containing the promoter region, when transfected into NMuLi cells, exhibited significant luciferase activity by comparison to a control plasmid. Troglitazone or troglitazone plus 9 -cis-RA significantly stimulated promoter activity expressed by the promoter containing a fragment of-2090bp or longer, but not -2005bp or shorter, indicating that the region between -2090 and -2006bp is responsible for the PPARg action. These results will facilitate understanding of the mechanism of PPARg action on ADRP expression. We are currently examining physiological significance of ADRP in thyrocytes and regulation of autoimmune thyroid diseases.

为了寻找自身免疫性甲状腺疾病的新治疗策略，我们研究了脂肪分化相关蛋白（ADRP），它最初被确定为脂肪细胞分化程序的早期标记物。该蛋白普遍表达，参与脂质储存和长链脂肪酸摄取。由于游离脂肪酸可能是炎症反应的中介，我们旨在揭示ADRP基因表达的调控机制。本研究揭示了小鼠ADRP基因的表达受PPARg调控。由此可见，PPARg配体、曲格列酮、吡格列酮和15 -脱氧- d12,14 -前列腺素J2可提高NMuLi小鼠肝细胞和J774.1小鼠巨噬细胞ADRP mRNA水平。放线菌素d完全抑制了这种增加，相反，PPARa配体非诺贝特和贝扎贝特未能增加mRNA水平。为了描述引起这种pparg诱导刺激的启动子区域，我们克隆了小鼠ADRP基因约2.8kb的5'侧区域，并构建了荧光素酶报告质粒用于评估启动子活性。当转染到NMuLi细胞时，与对照质粒相比，所有含有启动子区域的嵌合构建体都表现出显著的荧光素酶活性。曲格列酮或曲格列酮加9 -顺式ra显著刺激含有-2090bp或更长片段的启动子表达的启动子活性，而不含-2005bp或更短片段的启动子，表明-2090至-2006bp之间的区域负责PPARg作用。这些结果将有助于理解PPARg作用于ADRP表达的机制。我们目前正在研究ADRP在甲状腺细胞和自身免疫性甲状腺疾病调节中的生理意义。