Zinc finger protein 407 overexpression upregulates PPAR target gene expression and improves glucose homeostasis in mice
Zinc finger protein 407 overexpression upregulates PPAR target gene expression and improves glucose homeostasis in mice
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DOI：
10.1152/ajpendo.00234.2016
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发表时间：
2016-11-01
影响因子：
5.1
通讯作者：
Buchner, David A.
中科院分区：
文献类型：
--
作者：
Charrier, Alyssa;Wang, Li;Buchner, David A.
核受体的过氧化物酶体增殖物激活受体（PPAR）家族通过受体调节参与葡萄糖稳态、脂肪生成和脂质代谢的基因的表达的能力而对代谢疾病的病理生理学和治疗至关重要。然而，PPAR的调节机制仍不完全清楚。我们产生了主要在肌肉和心脏中过表达Zfp 407的转基因小鼠品系（ZFP-TG）。通过RNA-Seq进行的转录组分析确定了ZFP-TG小鼠肌肉中1，300个差异表达的基因，其中PPAR靶基因显著富集。在生理学上重要的PPAR γ靶基因中，葡萄糖转运蛋白（Glut）-4 mRNA和蛋白水平在心脏和肌肉中增加。相对于对照同窝仔，Zfp 407过表达的Glut 4和其他转录效应的增加一起降低了体重并降低了血糖、胰岛素和HOMA-IR评分。当被置于高脂肪饮食中时，ZFP-TG小鼠比野生型小鼠保持更高的葡萄糖耐受性。基于细胞的测定表明，Zfp 407协同地增加了所有PPAR亚型（PPARalpha、PPARgamma和PPARdelta）的转录活性。增加的PPAR活性与增加的PPARmRNA或蛋白水平无关，表明Zfp 407对PPAR活性具有后调节作用。总的来说，这些结果证明Zfp 407过表达改善了葡萄糖稳态。因此，Zfp 407代表了治疗代谢性疾病的新的药物靶标。
The peroxisome proliferator-activated receptor (PPAR) family of nuclear receptors is central to the pathophysiology and treatment of metabolic disease through the receptors' ability to regulate the expression of genes involved in glucose homeostasis, adipogenesis, and lipid metabolism. However, the mechanism by which PPAR is regulated remains incompletely understood. We generated a transgenic mouse strain (ZFP-TG) that overexpressed Zfp407 primarily in muscle and heart. Transcriptome analysis by RNA-Seq identified 1,300 differentially expressed genes in the muscle of ZFP-TG mice, among which PPAR target genes were significantly enriched. Among the physiologically important PPAR gamma target genes, Glucose transporter (Glut)-4 mRNA and protein levels were increased in heart and muscle. The increase in Glut4 and other transcriptional effects of Zfp407 overexpression together decreased body weight and lowered plasma glucose, insulin, and HOMA-IR scores relative to control littermates. When placed on high-fat diet, ZFP-TG mice remained more glucose tolerant than their wild-type counterparts. Cell-based assays demonstrated that Zfp407 synergistically increased the transcriptional activity of all PPAR subtypes, PPAR alpha, PPAR gamma, and PPAR delta. The increased PPAR activity was not associated with increased PPAR mRNA or protein levels, suggesting that Zfp407 posttranslationally regulates PPAR activity. Collectively, these results demonstrate that Zfp407 overexpression improved glucose homeostasis. Thus, Zfp407 represents a new drug target for treating metabolic disease.