Bile acid stimulates hepatocyte polarization through a cAMP-Epac-MEK-LKB1-AMPK pathway
Bile acid stimulates hepatocyte polarization through a cAMP-Epac-MEK-LKB1-AMPK pathway
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DOI：
10.1073/pnas.1018376108
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发表时间：
2011-01-25
影响因子：
11.1
通讯作者：
Arias, Irwin M.
中科院分区：
文献类型：
--
作者：
Fu, Dong;Wakabayashi, Yoshiyuki;Arias, Irwin M.
本研究描述了牛磺胆酸盐在胆小管形成中的独特功能，涉及通过cAMP-Epac-MEK-Rap 1-LKB 1-AMPK通路的信号传导。在大鼠肝细胞夹心培养中，极化表现为胆小管从小结构到完全分支网络的顺序进展。牛磺胆酸钠加速小管网络的形成，并伴随着增加cAMP，这是由腺苷酸环化酶抑制剂阻止。cAMP依赖性PKA抑制剂不能阻止牛磺胆酸盐的作用。相反，激活Epac，另一个cAMP下游激酶，加速小管网络的形成类似于牛磺胆酸盐的效果。抑制Epac下游靶点Rap 1和MEK，阻断了牛磺胆酸盐的作用。牛磺胆酸盐迅速激活MEK、LKB 1和AMPK，而这些激活可通过抑制腺苷酸环化酶或MEK来阻止。我们前期的研究表明，活化的LKB 1和AMPK参与小管网络的形成。胆汁酸合成、肝细胞极化和能量代谢调节之间的联系在正常肝细胞发育和疾病中可能是重要的。
This study describes a unique function of taurocholate in bile canalicular formation involving signaling through a cAMP-Epac-MEK-Rap1-LKB1-AMPK pathway. In rat hepatocyte sandwich cultures, polarization was manifested by sequential progression of bile canaliculi from small structures to a fully branched network. Taurocholate accelerated canalicular network formation and concomitantly increased cAMP, which were prevented by adenyl cyclase inhibitor. The cAMP-dependent PKA inhibitor did not prevent the taurocholate effect. In contrast, activation of Epac, another cAMP downstream kinase, accelerated canalicular network formation similar to the effect of taurocholate. Inhibition of Epac downstream targets, Rap1 and MEK, blocked the taurocholate effect. Taurocholate rapidly activated MEK, LKB1, and AMPK, which were prevented by inhibition of adenyl cyclase or MEK. Our previous study showed that activated-LKB1 and AMPK participate in canalicular network formation. Linkage between bile acid synthesis, hepatocyte polarization, and regulation of energy metabolism is likely important in normal hepatocyte development and disease.