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 secretion in 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.

中文翻译：

---

穿心莲内酯调节赋予肝代谢的HNF4α活性。

肝核因子4α（HNF4α）驱动载脂蛋白B（ApoB），微粒体甘油三酸酯转移蛋白（MTP）和磷脂酶A2 G12B（PLA2G12B）的表达，控制着肝脏极低密度脂蛋白（VLDL）的产生和分泌。穿心莲内酯（AP）是从穿心莲中分离出的主要成分。我们发现AP可以破坏HNF4α及其辅激活物过氧化物酶体增殖物激活受体γ辅激活物1-alpha（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对于与AP结合至关重要。由于拮抗HNF4α的活性，AP可抑制ApoB，MTP和PLA2G12B的表达，并降低体内肝VLDL的分泌速率。AP还通过下调HNF4α目标基因磷酸烯醇丙酮酸羧化激酶（Pepck）和葡萄糖-6-磷酸酶（G6pc）的表达来减少糖异生。总的来说，我们的结果表明AP通过调节HNF4α的转录活性影响肝功能。