Activation of farnesoid X receptor promotes triglycerides lowering by suppressing phospholipase A2 G12B expression
Activation of farnesoid X receptor promotes triglycerides lowering by suppressing phospholipase A2 G12B expression
复制标题
法尼醇 X 受体的激活通过抑制磷脂酶 A2 G12B 表达促进甘油三酯降低
DOI：
10.1016/j.mce.2016.07.027
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发表时间：
2016-11-15
影响因子：
4.1
通讯作者：
Guan, Min
中科院分区：
文献类型：
--
作者：
Liu, Qingli;Yang, Meng;Guan, Min
磷脂酶A2 G12 B（PLA 2 G12 B）是一种新型的肝细胞极低密度脂蛋白（VLDL）分泌调节因子，受肝细胞核因子-4 α（HNF-4 α）的转录调控。法尼酯X受体（FXR）在维持胆汁酸和甘油三酯（TG）的稳态中起着关键作用。在这里，我们报告，FXR调节血清TG水平的一部分，通过PLA 2G 12 B。鹅去氧胆酸（CDCA）或GW 4064激活FXR可显著降低HepG 2细胞中PLA 2G 12 B的表达。PLA 2G 12 B的表达由于FXR介导的小异源二聚体伴侣（SHP）的上调而被转录抑制，所述小异源二聚体伴侣（SHP）在功能上抑制HNF-4 α活性。我们发现用CDCA处理的高脂饮食小鼠肝脏PLA 2G 12 B表达被抑制，血清TG水平降低。同时，CDCA治疗降低肝脏VLDL-TG分泌。我们的数据表明，FXR的激活促进TG降低，不仅通过减少从头脂肪生成，而且还通过抑制PLA 2G 12 B表达减少富含TG的VLDL颗粒的肝脏分泌。(C)2016爱思唯尔爱尔兰有限公司版权所有。
As a novel mediator of hepatic very low-density lipoproteins (VLDL) secretion, phospholipase A2 G12B (PLA2G12B) is transcriptionally regulated by hepatocyte nuclear factor-4 alpha (HNF-4 alpha). Farnesoid X receptor (FXR) plays a critical role in maintaining bile acids and triglycerides (TG) homeostasis. Here we report that FXR regulates serum TG level in part through PLA2G12B. Activation of FXR by chenodeoxycholic acid (CDCA) or GW4064 significantly decreased PLA2G12B expression in HepG2 cells. PLA2G12B expression was transcriptionally repressed due to an FXR-mediated up-regulation of small heterodimer partner (SHP) which functionally suppresses HNF-4 alpha activity. We found that hepatic PLA2G12B expression was suppressed and serum TG level reduced in high fat diet mice treated with CDCA. Concurrently, CDCA treatment lowered hepatic VLDL-TG secretion. Our data demonstrate that activation of FXR promotes TG lowering, not only by decreasing de novo lipogenesis but also reducing hepatic secretion of TG-rich VLDL particles in part through suppressing PLA2G12B expression. (C) 2016 Elsevier Ireland Ltd. All rights reserved.