Bile acids induce hepatic stellate cell proliferation via activation of the epidermal growth factor receptor
Bile acids induce hepatic stellate cell proliferation via activation of the epidermal growth factor receptor
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DOI：
10.1053/j.gastro.2005.01.007
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发表时间：
2005-04-01
期刊：
影响因子：
29.4
通讯作者：
Moshage, H
中科院分区：
文献类型：
--
作者：
Svegliati-Baroni, G;Ridolfi, F;Moshage, H
背景与目的：肝星状细胞（HSC）增殖是肝纤维化发生发展的关键。在许多肝脏疾病中，HSC暴露于炎性细胞因子、活性氧和胆汁酸。虽然已知炎性细胞因子和活性氧促进HSC的增殖，但关于胆汁酸对HSC增殖或凋亡的影响还不清楚。本研究旨在探讨胆汁酸对肝星状细胞增殖的影响。方法：将HSC暴露于不同疏水性的胆汁酸（5-200 μ mol/L）中。通过溴脱氧尿苷掺入、细胞计数、增殖细胞核抗原和细胞周期蛋白E表达、caspase-3活性测定、活性caspase-3和吖啶橙子染色的免疫细胞化学、磷酸化特异性抗体的Western印迹检测信号转导通路的活化来评估HSC增殖和细胞周期相关事件。使用荧光胆汁酸研究胆汁酸的摄取。结果如下：浓度> 25 μ mol/L的所有胆汁酸通过激活表皮生长因子受体诱导HSC增殖增加2.5- 3倍。胆汁酸诱导的增殖是通过激活蛋白激酶C/细胞外信号调节激酶/p70（S6 K_）依赖性途径介导的。胆汁酸不诱导HSC凋亡。HSC不摄取荧光胆汁酸，也不表达胆汁酸输入物ntcp。结论：胆汁淤积状态下胆汁酸水平是一个独立的促纤维化因素。胆汁酸通过激活表皮生长因子受体诱导HSC增殖，而通过排除胆汁酸保护HSC免受胆汁酸诱导的凋亡。
Background & Aims: Hepatic stellate cell (HSC) proliferation is a key event in the development of liver fibrosis. In many liver diseases, HSCs are exposed to inflammatory cytokines, reactive oxygen species, and bile acids. Although inflammatory cytokines and reactive oxygen species are known to promote proliferation of HSCs, nothing is known about the effects of bile acids on HSC proliferation or apoptosis. The aim of this study was to investigate the effects of bile acids on HSC proliferation. Methods: HSCs were exposed to bile acids with different hydrophobicity (5-200 mu mol/L). HSC proliferation and cell cycle-related events were assessed by bromodeoxyuridine incorporation, cell counting and proliferating cell nuclear antigen and cyclin E expression, apoptosis by caspase-3 activity assay, immunocytochemistry for active caspase-3 and acridine orange staining, and activation of signal transduction pathways by Western blot using phospho-specific antibodies. Uptake of bile acids was investigated using fluorescent bile acids. Results: All bile acids, at concentrations > 25 mu mol/L, induce a 2.5- to 3-fold increase in HSC proliferation via activation of the epidermal growth factor receptor. Bile acid-induced proliferation is mediated by activation of a protein kinase C/extracellular signal-regulated kinase/p70(S6K_) dependent pathway. Bile acids did not induce apoptosis in HSCs. HSCs do not take up fluorescent bile acids and do not express the bile acid importer ntcp. Conclusions: Bile acids at levels reached in cholestatic conditions are an independent profibrogenic factor. Bile acids induce HSC proliferation via the activation of the epidermal growth factor receptor, whereas HSCs are protected against bile acid-induced apoptosis by excluding bile acids.