Bile acids enhance the activity of the insulin receptor and glycogen synthase in primary rodent hepatocytes
Bile acids enhance the activity of the insulin receptor and glycogen synthase in primary rodent hepatocytes
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DOI：
10.1002/hep.20043
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发表时间：
2004-02-01
期刊：
影响因子：
13.5
通讯作者：
Dent, P
中科院分区：
文献类型：
--
作者：
Han, SL;Studer, E;Dent, P
以前，我们证明，脱氧胆酸（DCA）诱导的ERK 1/2和AKT信号在原代肝细胞是一种保护性反应。在本研究中，我们研究了胆汁酸对磷脂酰肌醇3（PI 3）激酶/AKT/糖原合成酶（激酶）3（GSK 3）/糖原合成酶（GS）通路的调节。在原代肝细胞中，DCA激活ERBB 1（表皮生长因子受体）、ERBB 2和胰岛素受体，但不激活胰岛素样生长因子1（IGF-1）受体。DCA诱导的胰岛素受体激活与胰岛素受体底物1磷酸化增强相关，胰岛素受体抑制剂AG 1024和显性负性IGF-1受体（K1003 R）的表达均阻断了这种效应，显性负性IGF-1受体（K1003 R）的表达也抑制了DCA诱导的AKT激活。胆汁酸诱导的AKT活化和GSK 3磷酸化被ERBB 1抑制剂AG 1478钝化，并被AG 1024消除。胆汁酸导致GS活化至胰岛素（50 nM）诱导的相似水平;两者均通过抑制胰岛素受体功能和PI 3激酶/AK-T/GSK 3途径阻断。总之，这些研究结果表明，胆汁酸和胰岛素可能合作，以调节肝细胞中的葡萄糖储存。
Previously, we demonstrated that deoxycholic acid (DCA)-induced ERK1/2 and AKT signaling in primary hepatocytes is a protective response. In the present study, we examined the regulation of the phosphatidylinositol 3 (PI3) kinase/AKT/glycogen synthase (kinase) 3 (GSK3)/glycogen synthase (GS) pathway by bile acids. In primary hepatocytes, DCA activated ERBB1 (the epidermal growth factor receptor), ERBB2, and the insulin receptor, but not the insulin-like growth factor 1 (IGF-1) receptor. DCA-induced activation of the insulin receptor correlated with enhanced phosphorylation of insulin receptor substrate 1, effects that were both blocked by the insulin receptor inhibitor AG1024 and by expression of the dominant negative IGF-1 receptor (K1003R), which inhibited in trans. Expression of the dominant negative IGF-1 receptor (K1003R) also abolished DCA-induced AKT activation. Bile acid-induced activation of AKT and phosphorylation of GSK3 were blunted by the ERBB1 inhibitor AG1478 and abolished by AG1024. Bile acids caused activation of GS to a similar level induced by insulin (50 nM); both were blocked by inhibition of insulin receptor function and the PI3 kinase/AK-T/GSK3 pathway. In conclusion, these findings suggest that bile acids and insulin may cooperate to regulate glucose storage in hepatocytes.