The p300 Acetylase Is Critical for Ligand-activated Farnesoid X Receptor (FXR) Induction of SHP
The p300 Acetylase Is Critical for Ligand-activated Farnesoid X Receptor (FXR) Induction of SHP
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DOI：
10.1074/jbc.m803531200
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发表时间：
2008-12-12
影响因子：
4.8
通讯作者：
Kemper, Jongsook Kim
中科院分区：
文献类型：
--
作者：
Fang, Sungsoon;Tsang, Stephanie;Kemper, Jongsook Kim
主要的胆汁酸受体法尼西德X受体(FXR)通过调节许多胆汁酸反应基因的表达来维持血脂和血糖的动态平衡，包括孤儿核受体和代谢调节因子SHP。以SHP为模型基因，研究了P300乙酰化酶对FXR活性的调控。在小鼠肝脏和HepG2细胞中，FXR激动剂增加了FXR与p300的相互作用及其在SHP启动子上的募集和启动子上的乙酰化组蛋白水平。相反，在FXR基因缺失的小鼠中，没有检测到p300在启动子上的重新募集和乙酰化组蛋白。P300在体外直接与FXR相互作用并乙酰化FXR。野生型p300的过表达增加，而催化失活的p300突变体减少，乙酰化FXR水平和细胞内FXR反式激活。而相关的乙酰酶CBP，GCN5不促进FXR的反式激活，FXR激动剂也不增加其对启动子的募集，提示乙酰酶在FXR信号转导中具有功能特异性。通过siRNA下调p300，可降低乙酰化FXR和乙酰化组蛋白水平，并减少FXR在启动子上的占有率，从而显著抑制SHP的表达。这些结果表明，p300通过乙酰化启动子上的组蛋白和FXR本身，在FXR诱导SHP的过程中起着关键的辅助激活作用。令人惊讶的是，p300下调改变了与脂蛋白和葡萄糖代谢有关的其他代谢FXR靶基因的表达，从而有望获得有益的脂肪和葡萄糖图谱。这些意想不到的发现表明，抑制肝脏p300活性可能有利于治疗代谢性疾病。
The primary bile acid receptor farnesoid X receptor (FXR) maintains lipid and glucose homeostasis by regulating expression of numerous bile acid-responsive genes, including an orphan nuclear receptor and metabolic regulator SHP. Using SHP as a model gene, we studied how FXR activity is regulated by p300 acetylase. FXR interaction with p300 and their recruitment to the SHP promoter and acetylated histone levels at the promoter were increased by FXR agonists in mouse liver and HepG2 cells. In contrast, p300 recruitment and acetylated histones at the promoter were not detected in FXR-null mice. p300 directly interacted with and acetylated FXR in vitro. Overexpression of p300 wild type increased, whereas a catalytically inactive p300 mutant decreased, acetylated FXR levels and FXR transactivation in cells. While similar results were observed with a related acetylase, CBP, GCN5 did not enhance FXR transactivation, and its recruitment to the promoter was not increased by FXR agonists, suggesting functional specificity of acetylases in FXR signaling. Down-regulation of p300 by siRNA decreased acetylated FXR and acetylated histone levels, and occupancy of FXR at the promoter, resulting in substantial inhibition of SHP expression. These results indicate that p300 acts as a critical coactivator of FXR induction of SHP by acetylating histones at the promoter and FXR itself. Surprisingly, p300 down-regulation altered expression of other metabolic FXR target genes involved in lipoprotein and glucose metabolism, such that beneficial lipid and glucose profiles would be expected. These unexpected findings suggest that inhibition of hepatic p300 activity may be beneficial for treating metabolic diseases.