Caffeine protects against alcohol-induced liver fibrosis by dampening the cAMP/PKA/CREB pathway in rat hepatic stellate cells
Caffeine protects against alcohol-induced liver fibrosis by dampening the cAMP/PKA/CREB pathway in rat hepatic stellate cells
复制标题
咖啡因通过抑制大鼠肝星状细胞中的 cAMP/PKA/CREB 通路来预防酒精诱导的肝纤维化
DOI：
10.1016/j.intimp.2015.02.012
复制
发表时间：
2015-04-01
影响因子：
5.6
通讯作者：
Lv, Xiongwen
中科院分区：
文献类型：
--
作者：
Wang, Qi;Dai, Xuefei;Lv, Xiongwen
酒精性肝纤维化(ALF)是以长期酒精刺激下细胞外基质增生为特征的疾病。肝星状细胞(HSC)的激活在促进肝纤维化形成中起重要作用。咖啡因作为咖啡和茶中的主要活性成分，在日常生活中被广泛消费。人们一直认为咖啡因可以降低患肝病的几率。在这项研究中，我们试图验证咖啡因抑制从大鼠ALF模型中分离的HSCs激活的假设。用乙醇灌胃建立ALF模型，分别给予不同浓度的咖啡因或秋水仙碱治疗。测定血清丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)、透明质酸添加(HA)、层粘连蛋白(LN)、III型前胶原N端肽(PIIINP)和IV型胶原(CIV)的含量。取肝组织行苏木精-伊红染色和天狼星红染色。其他组通过肝脏灌流分离大鼠原代HSCs。有趣的是，我们发现咖啡因显著降低ALF模型大鼠的ALT、AST、HA、LN、PIIINP和CIV水平，并逆转肝纤维化。免疫组织化学、实时荧光定量聚合酶链式反应和免疫印迹结果表明，咖啡因可减轻HSC纤维化，抑制HSC内cAMP/PKA/CREB信号通路，咖啡因对ALF有预防作用。其机制可能与咖啡因通过腺苷A2a受体抑制HSC内cAMP/PKA/CREB信号通路有关。(C)2015爱思唯尔B.V.保留所有权利。
Alcoholic liver fibrosis (ALF) is characterized by hyperplasia of extracellular matrix under long-term alcohol stimulation. Hepatic stellate cell (HSC) activation plays an important role in promoting hepatic fibrogenesis. Caffeine, as the main active component of coffee and tea, was widely consumed in daily life. It was always a thought that caffeine can reduce the probability of suffering from liver diseases. In this study, we attempt to validate the hypothesis that caffeine inhibits activation of HSCs which were isolated from rat ALF model. The rats were gavaged by ethanol to establish ALF model and then treated with different concentrations of caffeine or colchicine. Serum was collected to measure the contents of serum alanine aminotransferase (ALT), aspartate transaminase (AST), hyaluronic add (HA), laminin (LN), N-terminal peptide of type III procollagen (PIIINP) and type IV collagen (CIV). Then liver tissues were obtained for hematoxylin-eosin staining and Sirius-red staining. Others were treated through liver perfusion to isolate primary rat HSCs. Interestingly, we found that caffeine significantly decreased ALT, AST, HA, LN, PIIINP and CIV levels and reversed liver fibrosis in rat ALF models. Results of immunohistochemistry, real-time PCR and western blot indicated that caffeine could reduce fibrosis and inhibit cAMP/PKA/CREB signal pathway in HSC Caffeine has a preventive effect on ALF. The mechanism may be interpreted that caffeine inhibits the cAMP/PKA/CREB signal pathway through adenosine A2A receptors in HSC. (C) 2015 Elsevier B.V. All rights reserved.