Bile acids regulate hepatic gluconeogenic genes and farnesoid X receptor via G(alpha)i-protein-coupled receptors and the AKT pathway.
Bile acids regulate hepatic gluconeogenic genes and farnesoid X receptor via G(alpha)i-protein-coupled receptors and the AKT pathway.
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DOI：
10.1194/jlr.m004929
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发表时间：
2010-08
影响因子：
6.5
通讯作者：
Hylemon PB
中科院分区：
文献类型：
--
作者：
Cao R;Cronk ZX;Zha W;Sun L;Wang X;Fang Y;Studer E;Zhou H;Pandak WM;Dent P;Gil G;Hylemon PB
胆汁酸是重要的调节分子，可以激活肝脏和胃肠道中的特异性核受体和细胞信号传导途径。本研究以慢性胆瘘（CBF）大鼠模型和原代大鼠肝细胞（PRH）为研究对象，探讨牛磺胆酸（TCA）对促肝细胞凋亡基因磷酸烯醇式丙酮酸羧激酶（PEPCK）、葡萄糖-6-磷酸酶（G-6-phosphatase，G-6-phosphatase）和编码短异源二聚体伴侣（SHP）基因的调控作用。将TCA肠内输注到CBF大鼠中迅速（1 h）激活AKT（约19倍）和ERK 1/2（3 - 5倍）信号通路，下调（约50%，30 min）PEPCK和G-6-ERK的mRNA水平，并诱导（3 h内14倍）SHP mRNA。TCA可迅速（约50%，1 - 2 h）下调PRH中PEPCK和G-6-β mRNA水平。用百日咳毒素（PTX）预处理PRH可阻断TCA对这些基因的下调。在PRH中，TCA加胰岛素显示出比单独使用更强的对乳酸和丙酮酸葡萄糖分泌/合成的抑制作用。PRH中SHP mRNA的诱导被特异性化学抑制剂抑制PI3激酶或PKC β或重组慢病毒编码的siRNA敲低PKC β强烈阻断。胰岛素信号通路的激活似乎与法尼醇X受体功能活性的上调和SHP诱导有关。
Bile acids are important regulatory molecules that can activate specific nuclear receptors and cell signaling pathways in the liver and gastrointestinal tract. In the current study, the chronic bile fistula (CBF) rat model and primary rat hepatocytes (PRH) were used to study the regulation of gluconeogenic genes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G-6-Pase) and the gene encoding short heterodimeric partner (SHP) by taurocholate (TCA). The intestinal infusion of TCA into the CBF rat rapidly (1 h) activated the AKT (∼9-fold) and ERK1/2 (3- to 5-fold) signaling pathways, downregulated (∼50%, 30 min) the mRNA levels of PEPCK and G-6-Pase, and induced (14-fold in 3 h) SHP mRNA. TCA rapidly (∼50%, 1–2 h) downregulated PEPCK and G-6-Pase mRNA levels in PRH. The downregulation of these genes by TCA was blocked by pretreatment of PRH with pertussis toxin (PTX). In PRH, TCA plus insulin showed a significantly stronger inhibition of glucose secretion/synthesis from lactate and pyruvate than either alone. The induction of SHP mRNA in PRH was strongly blocked by inhibition of PI3 kinase or PKCζ by specific chemical inhibitors or knockdown of PKCζ by siRNA encoded by a recombinant lentivirus. Activation of the insulin signaling pathway appears to be linked to the upregulation of farnesoid X receptor functional activity and SHP induction.