Corepressors selectively control the transcriptional activity of PPARγ in adipocytes
Corepressors selectively control the transcriptional activity of PPARγ in adipocytes
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DOI：
10.1101/gad.1263305
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发表时间：
2005-02-15
影响因子：
10.5
通讯作者：
Lazar, MA
中科院分区：
文献类型：
--
作者：
Guan, HP;Ishizuka, T;Lazar, MA
过氧化物酶体增殖物激活受体-γ(PPAR-γ)是脂肪形成的主要调节因子，也是噻唑烷二酮(TZD)抗糖尿病药物的靶点。许多PPARGamma靶基因在脂肪形成过程中被诱导，但另一些基因，如甘油激酶(GyK)，在脂肪细胞中低水平表达，并被TZDS显著上调。在这里，我们探索了脂肪细胞基因表达选择性地需要外源PPARγ配体的机制。GyK基因包含一个功能性的PPAR-伽马反应元件，内源性PPAR-伽马被脂肪细胞招募到该元件上。然而，与经典的PPAR伽马靶基因aP2不同，GyK基因是脂肪细胞中核受体辅阻遏物的靶向基因。TZD可激活辅阻遏子组蛋白脱乙酰酶(HDAC)复合体的解离和GyK基因辅活化子的募集。TZDS还诱导PPAR-辅活化子1α(PGC-1α)，PGC-1α对GyK基因的募集足以释放辅阻遏子。因此，TZDS对脂肪细胞PPARGamma靶基因的选择性调控涉及到通过直接和间接机制解离辅阻遏子。
Peroxisome proliferator-activated receptor gamma (PPAR-gamma) is the master regulator of adipogenesis as well as the target of thiazolidinedione (TZD) antidiabetic drugs. Many PPARgamma target genes are induced during adipogenesis, but others, such as glycerol kinase (GyK), are expressed at low levels in adipocytes and dramatically up-regulated by TZDs. Here, we have explored the mechanism whereby an exogenous PPARgamma ligand is selectively required for adipocyte gene expression. The GyK gene contains a functional PPAR-gamma-response element to which endogenous PPARgamma is recruited in adipocytes. However, unlike the classic PPARgamma-target gene aP2, which is constitutively associated with coactivators, the GyK gene is targeted by nuclear receptor corepressors in adipocytes. TZDs trigger the dismissal of corepressor histone deacetylase (HDAC) complexes and the recruitment of coactivators to the GyK gene. TZDs also induce PPARgamma-Coactivator 1alpha (PGC-1alpha), whose recruitment to the GyK gene is sufficient to release the corepressors. Thus, selective modulation of adipocyte PPARgamma target genes by TZDs involves the dissociation of corepressors by direct and indirect mechanisms.