Hormonal Modulation of Hepatic cAMP Prevents Estradiol 17β-d-Glucuronide-Induced Cholestasis in Perfused Rat Liver
Hormonal Modulation of Hepatic cAMP Prevents Estradiol 17β-d-Glucuronide-Induced Cholestasis in Perfused Rat Liver
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肝 cAMP 的激素调节可预防雌二醇 17β-d-葡萄糖醛酸苷诱导的大鼠灌注肝脏胆汁淤积
DOI：
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发表时间：
2013
影响因子：
3.1
通讯作者：
E. J. Sánchez Pozzi
中科院分区：
文献类型：
--
作者：
A. Zucchetti;I. Barosso;Andrea C. Boaglio;M. Luquita;M. Roma;F. Crocenzi;E. J. Sánchez Pozzi
背景E17 β-D-葡萄糖醛酸苷（E17 G）在体内诱导胆汁淤积，小管转运蛋白多药耐药相关蛋白2（Abcc 2）和胆盐输出泵（Abcb 11）的内吞内化是其重要的病理机制。环磷酸腺苷（cAMP）通过将这些转运蛋白靶向回到小管膜来防止胆汁淤积。在肝细胞偶联中，胰高血糖素和沙丁胺醇（两者均增加cAMP）通过不同的机制刺激这些转运蛋白的运输来阻止E17 G的作用，即：胰高血糖素激活蛋白激酶A依赖性途径，而沙丁胺醇激活由cAMP（Epac）介导激活的交换蛋白，方法本研究评价胰高血糖素和沙丁胺醇是否在更生理的模型中预防E17 G诱导的胆汁淤积，即，灌注大鼠肝脏（PRL）。此外，在体内丙氨酸管理，诱导胰腺胰高血糖素分泌的预防效果进行了evaluated.ResultsIn催乳素，胰高血糖素和沙丁胺醇防止E17 G诱导的胆汁流量和分泌活动的Abcc 2和Abcb 11的减少。沙丁胺醇的预防完全依赖于微管的完整性。另一方面，胰高血糖素的预防作用仅在E17 G给药后的早期阶段是微管非依赖性的，但它最终受到微管破坏剂秋水仙碱的影响。胆汁淤积与Abcb 11和Abcc 2的内吞内化相关，细胞内载体与内体标记Rab 11 a部分共定位。沙丁胺醇完全阻止了这种作用，而胰高血糖素治疗后，一些含有转运蛋白的囊泡仍然与Rab 11 a共定位。在体内，丙氨酸给药增加肝cAMP和加速胆汁流量和Abcb 11/Abcc 2转运功能的恢复后，E17 G给药。丙氨酸提供的初始恢复是微管无关的，但微管的完整性是需要维持这种保护作用。结论我们得出结论，cAMP水平的调制无论是通过直接管理的cAMP调节剂或通过生理操作导致的cAMP水平的增加，（丙氨酸施用），在具有保留的肝脏结构的模型中预防雌激素诱导的胆汁淤积，通过与体外研究相似的机制。
BackgroundEstradiol-17β-d-glucuronide (E17G) induces cholestasis in vivo, endocytic internalization of the canalicular transporters multidrug resistance-associated protein 2 (Abcc2) and bile salt export pump (Abcb11) being a key pathomechanism. Cyclic AMP (cAMP) prevents cholestasis by targeting these transporters back to the canalicular membrane. In hepatocyte couplets, glucagon and salbutamol, both of which increase cAMP, prevented E17G action by stimulating the trafficking of these transporters by different mechanisms, namely: glucagon activates a protein kinase A-dependent pathway, whereas salbutamol activates an exchange-protein activated by cAMP (Epac)-mediated, microtubule-dependent pathway.MethodsThe present study evaluated whether glucagon and salbutamol prevent E17G-induced cholestasis in a more physiological model, i.e., the perfused rat liver (PRL). Additionally, the preventive effect of in vivo alanine administration, which induces pancreatic glucagon secretion, was evaluated.ResultsIn PRLs, glucagon and salbutamol prevented E17G-induced decrease in both bile flow and the secretory activity of Abcc2 and Abcb11. Salbutamol prevention fully depended on microtubule integrity. On the other hand, glucagon prevention was microtubule-independent only at early time periods after E17G administration, but it was ultimately affected by the microtubule disrupter colchicine. Cholestasis was associated with endocytic internalization of Abcb11 and Abcc2, the intracellular carriers being partially colocalized with the endosomal marker Rab11a. This effect was completely prevented by salbutamol, whereas some transporter-containing vesicles remained colocalized with Rab11a after glucagon treatment. In vivo, alanine administration increased hepatic cAMP and accelerated the recovery of bile flow and Abcb11/Abcc2 transport function after E17G administration. The initial recovery afforded by alanine was microtubule-independent, but microtubule integrity was required to sustain this protective effect.ConclusionWe conclude that modulation of cAMP levels either by direct administration of cAMP modulators or by physiological manipulations leadings to hormone-mediated increase of cAMP levels (alanine administration), prevents estrogen-induced cholestasis in models with preserved liver architecture, through mechanisms similar to those arisen from in vitro studies.
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DOI：
10.1016/s0021-9258(18)54551-8
发表时间：
1991-11
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
C. A. Hinchman;H. Matsumoto;T. W. Simmons;N. Ballatori
通讯作者：
C. A. Hinchman;H. Matsumoto;T. W. Simmons;N. Ballatori
DOI：
10.1016/s0021-9258(18)32544-4
发表时间：
1983-04
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
N. Morgan;P. Blackmore;J. Exton
通讯作者：
N. Morgan;P. Blackmore;J. Exton
环 AMP 刺激小管有机阴离子转运蛋白 (Mrp2/cMoat) 分选至肝细胞对的顶端域。
影响因子：
4
作者：
Roelofsen,H;Soroka,CJ;Keppler,D;Boyer,JL
通讯作者：
Boyer,JL
影响因子：
3.3
作者：
Wakabayashi, Y;Lippincott-Schwartz, J;Arias, IM
通讯作者：
Arias, IM
影响因子：
29.4
作者：
Wang, Wei;Soroka, Carol J.;Boyer, James L.
通讯作者：
Boyer, James L.