Andrographolide modulates HNF4 alpha activity imparting on hepatic metabolism
Andrographolide modulates HNF4 alpha activity imparting on hepatic metabolism
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穿心莲内酯调节 HNF4 α 活性，影响肝脏代谢
DOI：
10.1016/j.mce.2020.110867
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发表时间：
2020
影响因子：
4.1
通讯作者：
Guan Min
中科院分区：
文献类型：
--
作者：
Zhang Minyi;Yang Meng;Wang Na;Liu Qingli;Wang Binxu;Huang Tongling;Tong Yan;Ming Yanlin;Wong Chi-Wai;Liu Jinsong;Yao Dongsheng;Guan Min
肝核因子4α (HNF4α)驱动载脂蛋白B （ApoB）、微粒体甘油三酯转移蛋白（MTP）和磷脂酶A2G12B （PLA2G12B）的表达，控制肝脏极低密度脂蛋白（VLDL）的产生和分泌。穿心莲内酯（Andrographolide， AP）是从穿心莲中分离得到的主要成分。我们发现AP可以破坏HNF4α与其辅助激活因子过氧化物酶体增殖体激活受体γ辅助激活因子1- α (PGC1α)之间的相互作用。虚拟对接和突变分析表明，HNF4α的精氨酸235是与AP结合所必需的。由于对抗HNF4α的活性，AP在体内抑制ApoB、MTP和PLA2G12B的表达，并降低肝脏VLDL的分泌率。AP还通过下调HNF4α靶基因磷酸烯醇丙酮酸羧激酶（Pepck）和葡萄糖-6-磷酸酶（G6pc）的表达来降低糖异生。总之，我们的研究结果表明，AP通过调节HNF4α的转录活性来影响肝功能。
Hepatic nuclear factor 4 alpha (HNF4α) drives the expression of apolipoprotein B (ApoB), microsomal triglyceride transfer protein (MTP) and phospholipase A2 G12B (PLA2G12B), governing hepatic very-low-density lipoprotein (VLDL) production and secretion. Andrographolide (AP) is a major constituent isolated from Andrographis paniculata. We found that AP can disrupt the interaction between HNF4α and its coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α). Virtual docking and mutational analysis indicated that arginine 235 of HNF4α is essential for binding to AP. As a consequence of antagonizing the activity of HNF4α, AP suppresses the expression of ApoB, MTP and PLA2G12B and reduces the rate of hepatic VLDL secretionin vivo. AP additionally reduced gluconeogenesis via down-regulating the expression of HNF4α target genes phosphoenolpyruvate carboxykinase (Pepck) and glucose-6-phosphatase (G6pc). Collectively, our results suggest that AP affects liver function via modulating the transcriptional activity of HNF4α.