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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >Phosphoinositide 3-kinase/protein kinase B signaling pathway is involved in estradiol 17beta-D-glucuronide-induced cholestasis: complementarity with classical protein kinase C.
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Phosphoinositide 3-kinase/protein kinase B signaling pathway is involved in estradiol 17beta-D-glucuronide-induced cholestasis: complementarity with classical protein kinase C.

机译：磷酸肌醇3激酶/蛋白激酶B信号通路参与雌二醇17β-D-葡糖醛酸诱导的胆汁淤积：与经典蛋白激酶C的互补性。

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摘要

Estradiol 17beta-D-glucuronide (E(2)17G) is an endogenous, cholestatic metabolite that induces endocytic internalization of the canalicular transporters relevant to bile secretion: bile salt export pump (Bsep) and multidrug resistance-associated protein 2 (Mrp2). We assessed whether phosphoinositide 3-kinase (PI3K) is involved in E(2)17G-induced cholestasis. E(2)17G activated PI3K according to an assessment of the phosphorylation of the final PI3K effector, protein kinase B (Akt). When the PI3K inhibitor wortmannin (WM) was preadministered to isolated rat hepatocyte couplets (IRHCs), it partially prevented the reduction induced by E(2)17G in the proportion of IRHCs secreting fluorescent Bsep and Mrp2 substrates (cholyl lysyl fluorescein and glutathione methylfluorescein, respectively). 2-Morpholin-4-yl-8-phenylchromen-4-one, another PI3K inhibitor, and an Akt inhibitor (Calbiochem 124005) showed similar protective effects. IRHC immunostaining and confocal microscopy analysis revealed that endocytic internalization of Bsep and Mrp2 induced by E(2)17G was extensively prevented by WM; this effect was fully blocked by the microtubule-disrupting agent colchicine. The protection of WM was additive to that afforded by the classical protein kinase C (cPKC) inhibitor 5,6,7,13-tetrahydro-13-methyl-5-oxo-12H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-12-p ropanenitrile (Go6976); this suggested differential and complementary involvement of the PI3K and cPKC signaling pathways in E(2)17G-induced cholestasis. In isolated perfused rat liver, an intraportal injection of E(2)17G triggered endocytosis of Bsep and Mrp2, and this was accompanied by a sustained decrease in the bile flow and the biliary excretion of the Bsep and Mrp2 substrates [(3)H]taurocholate and glutathione until the end of the perfusion period. Unlike Go6976, WM did not prevent the initial decay, but it greatly accelerated the recovery to normality of these parameters and the reinsertion of Bsep and Mrp2 into the canalicular membrane in a microtubule-dependent manner. CONCLUSION: The PI3K/Akt signaling pathway is involved in the biliary secretory failure induced by E(2)17G through sustained internalization of canalicular transporters endocytosed via cPKC.
机译：雌二醇17β-D-葡糖醛酸（E（2）17G）是一种内源性胆碱代谢产物，可诱导与胆汁分泌有关的小管转运蛋白的内吞性内化：胆盐输出泵（Bsep）和多药耐药相关蛋白2（Mrp2）。我们评估了磷酸肌醇3-激酶（PI3K）是否参与E（2）17G诱导的胆汁淤积。 E（2）17G根据最终PI3K效应子蛋白激酶B（Akt）磷酸化的评估激活了PI3K。当将PI3K抑制剂渥曼青霉素（WM）预先给药于离体大鼠肝细胞联（IRHC）时，它部分阻止了E（2）17G诱导的IRHC分泌荧光Bsep和Mrp2底物（胆甾醇赖氨酰荧光素和谷胱甘肽甲基荧光素，分别）。另一种PI3K抑制剂2-Morpholin-4-yl-8-phenylchromen-4-one和Akt抑制剂（Calbiochem 124005）显示出相似的保护作用。 IRHC免疫染色和共聚焦显微镜分析表明，WM广泛阻止了E（2）17G诱导的Bsep和Mrp2的内吞内在化。这种作用被微管破坏剂秋水仙碱完全阻断。 WM的保护是对经典蛋白激酶C（cPKC）抑制剂5,6,7,13-tetrahydro-13-methyl-5-oxo-12H-indolo [2,3-a] pyrrolo [3]提供的保护的，4-c]咔唑-12-对戊腈（Go6976）;这表明在E（2）17G诱发的胆汁淤积中，PI3K和cPKC信号通路的差异和互补参与。在离体灌流的大鼠肝脏中，经门静脉内注射E（2）17G会触发Bsep和Mrp2的内吞作用，并伴有胆汁流量的持续减少以及Bsep和Mrp2底物的胆汁排泄[[3）H]牛磺胆酸盐和谷胱甘肽直到灌注期结束。与Go6976不同，WM不能阻止初始衰减，但可以极大地加速这些参数恢复正常，并以微管依赖性方式将Bsep和Mrp2重新插入小管膜。结论：PI3K / Akt信号通路通过持续内在化通过cPKC的小管转运蛋白，参与E（2）17G诱导的胆道分泌衰竭。

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