The peroxisome proliferator-activated receptor γ regulates expression of the perilipin gene in adipocytes
The peroxisome proliferator-activated receptor γ regulates expression of the perilipin gene in adipocytes
复制标题
DOI：
10.1074/jbc.m308522200
复制
发表时间：
2004-03-12
影响因子：
4.8
通讯作者：
Sato, R
中科院分区：
文献类型：
--
作者：
Arimura, N;Horiba, T;Sato, R
最近的研究表明，脂滴被蛋白质外壳所覆盖，尽管组分蛋白质的功能和身份尚未得到很好的阐明。第一个确定的脂滴特异性蛋白质是周脂蛋白，一个蛋白质家族，覆盖脂肪细胞的脂滴表面。围脂蛋白缺失小鼠的产生表明，尽管它们比对照小鼠消耗更多的食物，但它们具有正常的体重，并且对饮食诱导的肥胖有抵抗力。在一项研究中（Martinez-Botas，J.，安德森，J. B.，Tessier，D.，Lapillonne，A.，张，B。H. J.，Quast，M. J.，Gorenstein，D.，Chen，K. H、和Chan，L.等人（2000）Nat.Genet. 26，474-479），据报道，在动物模型中，通过将周脂蛋白-/-等位基因繁殖到Lepr db/db肥胖小鼠中，表面上通过增加小鼠的代谢速率，肥胖是可逆的。为了理解驱动脂肪细胞中perilipin基因排他性表达的确切机制，我们分析了小鼠基因的5 '侧翼区。用增殖物激活受体（PPAR）γ激动剂处理分化的3 T3-L1脂肪细胞（公认的脂肪细胞分化的“主调节剂”），显著增强了围脂蛋白基因的表达。使用-2.0-kb启动子的报告基因分析显示，该区域含有功能性PPARgamma响应元件。凝胶迁移率变化和染色质免疫沉淀分析表明，内源性PPARgamma蛋白结合周脂蛋白启动子。PPARgamma 2是一种仅在脂肪细胞中表达的同种型，被发现是包括PPARalpha和PPARgamma 1的PPAR家族成员中最有效的调节剂。这些结果表明，分化脂肪细胞中的周脂蛋白基因表达受到PPARgamma 2的关键调节，这为PPARgamma 2的成脂作用和脂肪特异性基因表达以及针对减少的潜在抗肥胖药物提供了新的见解周脂蛋白基因产物。
Recent studies have shown that lipid droplets are covered with a proteinaceous coat, although the functions and identities of the component proteins have not yet been well elucidated. The first identified lipid droplet-specific proteins are the perilipins, a family of proteins coating the surfaces of lipid droplets of adipocytes. The generation of perilipin-null mice has revealed that although they consume more food than control mice, they have normal body weight and are resistant to diet-induced obesity. In one study (Martinez-Botas, J., Anderson, J. B., Tessier, D., Lapillonne, A., Chang, B. H. J., Quast, M. J., Gorenstein, D., Chen, K. H., and Chan, L. ( 2000) Nat. Genet. 26, 474-479) it was reported that in an animal model obesity was reversible by breeding perilipin -/- alleles into Lepr db/db obese mice, ostensibly by increasing the metabolic rate of the mice. To understand the exact mechanisms that drive the exclusive expression of the perilipin gene in adipocytes, we analyzed the 5'-flanking region of the mouse gene. Treatment of differentiating 3T3-L1 adipocytes with an agonist of proliferator-activated receptor ( PPAR) gamma, the putative "master regulator" of adipocyte differentiation, significantly augmented perilipin gene expression. Reporter assays using the -2.0-kb promoter revealed that this region contains a functional PPARgamma-responsive element. Gel mobility shift and chromatin immunoprecipitation assays showed that endogenous PPARgamma protein binds to the perilipin promoter. PPARgamma2, an isoform exclusively expressed in adipocytes, was found to be the most potent regulator from among the PPAR family members including PPARalpha and PPARgamma1. These results make evident the fact that perilipin gene expression in differentiating adipocytes is crucially regulated by PPARgamma2, providing new insights into the adipogenic action of PPARgamma2 and adipose-specific gene expression, as well as potential anti-obesity pharmaceutical agents targeted to a reduction of the perilipin gene product.