The flavonoid derivative 4'-nitro-6-hydroxyflavone suppresses the activity of HNF4α and stimulates the degradation of HNF4α protein through the activation of AMPK.
The flavonoid derivative 4'-nitro-6-hydroxyflavone suppresses the activity of HNF4α and stimulates the degradation of HNF4α protein through the activation of AMPK.
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类黄酮衍生物4-硝基-6-羟基黄酮可抑制HNF4α的活性，并通过激活AMPK刺激HNF4α蛋白的降解。
DOI：
10.1080/09168451.2017.1325316
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
R.
中科院分区：
文献类型：
--
作者：
Inoue;J.;Ikeda;S.;Kanayama;T.;and Sato;R.
肝细胞核因子4α（HNF 4 α）是一种核受体，调节参与许多关键代谢途径的基因表达。HNF 4 α活性的调节被认为是治疗高脂血症的一个有前途的药物靶向途径。为了鉴定降低HNF 4 α活性的化合物，我们使用微粒体甘油三酯转移蛋白（MTP）基因的启动子区（包含HNF 4 α反应元件）进行了荧光素酶报告基因试验。使用这个系统，我们在这里表明，类黄酮衍生物4′-硝基-6-羟基黄酮（NOHF）抑制MTP启动子活性。用NOHF处理引起HNF 4 α靶基因表达的降低。我们还发现NOHF可以激活AMP激活的蛋白激酶（AMPK），加速HNF 4 α蛋白的降解。AMPK的敲低减弱了NOHF的作用。这些结果表明，NOHF是AMPK激活剂，并且至少部分地通过加速HNF 4 α蛋白降解来减弱HNF 4 α的转录活性。
Hepatocyte nuclear factor 4α (HNF4α) is a nuclear receptor that regulates the expression of genes involved in a number of critical metabolic pathways. The modulation of HNF4α activity is thought to be a promising drug target pathway for hyperlipidemia. To identify compounds that reduce the activity of HNF4α, we conducted luciferase reporter assays using the promoter region of microsomal triglyceride transfer protein (MTP) gene, which contains an HNF4α-responsive element. Using this system, we show here that the flavonoid derivative 4′-nitro-6-hydroxyflavone (NOHF) suppresses MTP promoter activity. Treatment with NOHF caused a decrease in the expression of the HNF4α target gene. We also identified that NOHF triggers the AMP-activated protein kinase (AMPK) and accelerates the degradation of HNF4α protein. Knock-down of AMPK diminishes the effect of NOHF. These results indicate that NOHF is an AMPK activator and attenuates the transcriptional activity of HNF4α, at least in part, by accelerating HNF4α protein degradation.