18 beta-Glycyrrhetinic acid acts through hepatocyte nuclear factor 4 alpha to modulate lipid and carbohydrate metabolism
18 beta-Glycyrrhetinic acid acts through hepatocyte nuclear factor 4 alpha to modulate lipid and carbohydrate metabolism
复制标题
18 β-甘草次酸通过肝细胞核因子 4 α 调节脂质和碳水化合物代谢
DOI：
10.1016/j.phrs.2020.104840
复制
发表时间：
2020
影响因子：
9.3
通讯作者：
Guan Min
中科院分区：
文献类型：
--
作者：
Yang Meng;Zhang Minyi;Liu Qingli;Xu Tingting;Huang Tongling;Yao Dongsheng;Wong Chi-Wai;Liu Jinsong;Guan Min
肝细胞核因子4 α（HNF 4 α）调节参与极低密度脂蛋白（VLDL）稳态和新生血管形成的必需基因的表达。18β-甘草次酸（GA）是甘草中治疗肝营养不良的有效成分。本研究通过HNF 4 α驱动的报告基因荧光素酶实验和与共激活剂PGC 1 α的免疫共沉淀实验，证实GA具有部分拮抗HNF 4 α的功能。通过虚拟对接和定点突变分析，证实HNF 4 α的丝氨酸190和精氨酸235是GA发挥其拮抗作用所必需的。重要的是，GA抑制HNF 4 α靶基因的表达，如载脂蛋白B（Apo B）、微粒体甘油三酯转移蛋白（MTP）和磷脂酶A2 G12 B（PLA 2 G12 B），这些基因调节高脂饮食小鼠肝脏VLDL分泌。此外，GA还通过下调HNF 4 α靶基因葡萄糖-6-磷酸酶（G6 pc）和磷酸烯醇式丙酮酸羧激酶（Pepck）的表达，从而抑制肿瘤的发生，改善葡萄糖耐受不良。此外，GA还能显著降低血糖，改善胰岛素抵抗。总之，我们确定GA作为部分HNF 4 α拮抗剂调节脂质和碳水化合物代谢。
Hepatocyte nuclear factor 4 alpha (HNF4α) regulates the expression of essential genes involved in very-low-density lipoprotein (VLDL) homeostasis and gluconeogenesis. 18β-glycyrrhetinic acid (GA) is an active ingredient ofGlycyrrhiza uralensisan herbal medicine used for treating liver aliments. In this study, we established that GA functions as a partial antagonist of HNF4α through HNF4α-driven reporter luciferase assay and co-immunoprecipitation experiments with co-activator PGC1α. By virtual docking and site-directed mutagenesis analysis, we confirmed that serine 190 and arginine 235 of HNF4α are both essential for GA to exert its antagonistic action on HNF4α. Importantly, GA suppressed the expression of HNF4α target genes such as apolipoprotein B (ApoB), microsomal triglyceride transfer protein (MTP) and phospholipase A2G12B (PLA2G12B) modulating hepatic VLDL secretion in mice fed on a high fat diet. In addition, GA also suppressed gluconeogenesis and ameliorated glucose intolerance via down-regulating the expression of HNF4α target genes glucose-6-phosphatase (G6pc) and phosphoenolpyruvate carboxykinase (Pepck). Furthermore, GA significantly lowered blood glucose and improved insulin resistance indb/dbmice. In all, we established that GA acts as a partial HNF4α antagonist modulating lipid and carbohydrate metabolism.