The peroxisome proliferator-activated receptor N-terminal domain controls isotype-selective gene expression and adipogenesis
The peroxisome proliferator-activated receptor N-terminal domain controls isotype-selective gene expression and adipogenesis
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DOI：
10.1210/me.2006-0025
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发表时间：
2006-06-01
影响因子：
--
通讯作者：
Tontonoz, Peter
中科院分区：
文献类型：
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作者：
Hummasti, Sarah;Tontonoz, Peter
过氧化物酶体增殖物激活受体（PPARgamma、PPARgamma和PPARgamma）是脂质代谢的重要调节剂。虽然它们具有显著的结构相似性，但与每种PPAR同种型相关的生物学效应是不同的。例如，PPARalpha和PPARdelta调节脂肪酸催化剂，而PPARgamma控制脂质储存和脂肪生成。PPARs在体内的不同功能至少可以部分地由三种受体的不同组织分布来解释。然而，受体是否具有不同的内在活性并调节不同的靶基因的问题还没有得到充分的探讨。我们已经设计了表达相当数量的每种受体的细胞系。在选择性激动剂的存在下，这些细胞的转录谱揭示了三种PPARs的部分重叠但不同的基因调控模式。此外，嵌合受体的分析指出每个受体的N末端是同种型选择性基因表达的关键决定因素。例如，当与PPARdelta DNA结合结构域和配体结合结构域融合时，PPARgamma的N末端赋予促进脂肪细胞分化的能力，而当与PPARgamma融合时，PPARdelta的N末端导致脂肪酸氧化基因在分化的脂肪细胞中的不适当表达。最后，我们证明，每个受体的N末端的功能部分限制受体活性，因为N末端的缺失导致靶基因的非选择性激活。更详细地了解个别PPARs差异调节基因表达的机制，应有助于设计更有效的药物，包括组织和靶基因选择性的PPAR调节剂。
Peroxisome proliferator-activated receptors (PPAR gamma, PPAR gamma, and PPAR gamma) are important regulators of lipid metabolism. Although they share significant structural similarity, the biological effects associated with each PPAR isotype are distinct. For example, PPAR alpha and PPAR delta regulate fatty acid catabolism, whereas PPAR gamma controls lipid storage and adipogenesis. The different functions of PPARs in vivo can be explained at least in part by the different tissue distributions of the three receptors. The question of whether the receptors have different intrinsic activities and regulate distinct target genes, however, has not been adequately explored. We have engineered cell lines that express comparable amounts of each receptor. Transcriptional profiling of these cells in the presence of selective agonists reveals partially overlapping but distinct patterns of gene regulation by the three PPARs. Moreover, analysis of chimeric receptors points to the N terminus of each receptor as the key determinant of isotype-selective gene expression. For example, the N terminus of PPAR gamma confers the ability to promote adipocyte differentiation when fused to the PPAR delta DNA binding domain and ligand binding domain, whereas the N terminus of PPAR delta leads to the inappropriate expression of fatty acid oxidation genes in differentiated adipocytes when fused to PPAR gamma. Finally, we demonstrate that the N terminus of each receptor functions in part to limit receptor activity because deletion of the N terminus leads to nonselective activation of target genes. A more detailed understanding of the mechanisms by which the individual PPARs differentially regulate gene expression should aid in the design of more effective drugs, including tissue-and target gene- selective PPAR modulators.