β-arrestin1通过活化p38信号转导通路激活肝星状细胞促进肝纤维化  

β-arrestin1 activates hepatic stellate cells to promote liver fibrosis via activating p38 signaling pathway

作　　者：夏彦昊 刘慧玲[1] 江洁[1] 吴斌[1] Xia Yanhao;Liu Huiling;Jiang Jie;Wu Bin(Department of Gastroenterology,the Third Affiliated Hospital of Sun Yat-Sen University,Guangzhou 510630,China)

机构地区：[1]中山大学附属第三医院消化内科,广州510630

出　　处：《新医学》2023年第1期59-65,共7页Journal of New Medicine

摘　　要：目的 探讨β-arrestin1(ARRB1)在肝纤维化中的作用,阐明ARRB1和p38信号转导通路诱导肝星状细胞活化从而促进肝纤维化的机制。方法 选取C57BJ/6L背景的雄性小鼠12只,随机分为对照组和模型组,每组6只小鼠,采用浓度为20%的四氯化碳诱导肝纤维化小鼠模型,并于临床收集肝硬化患者的肝组织及健康对照志愿者的肝组织样本。采用HE和天狼星红染色来评估肝纤维化情况。通过免疫组织化学法、蛋白免疫印迹法及实时荧光定量PCR法检测ARRB1、p38、磷酸化p38(pp38)及纤维化相关指标α平滑肌肌动蛋白(α-SMA)和Ⅰ型胶原蛋白的表达水平。在人肝星状细胞LX2中使用转化生长因子-β(TGF-β)细胞因子诱导其活化,并分析ARRB1的表达水平;进而利用小干扰RNA和质粒沉默或者过表达ARRB1,同时配合p38特异性抑制剂(SB203580),揭示两者的调控关系。结果 在肝纤维化组织中ARRB1表达升高,p38信号活化增强(P均<0.05)。在肝星状细胞LX2中,TGF-β可以激活肝星状细胞并表达ARRB1和增强p38信号。ARRB1表达的升高或抑制可以相应地影响p38信号从而调节肝星状细胞活性,然而p38活性的变化并不影响ARRB1的表达。结论 在肝纤维化中,ARRB1表达升高,通过活化p38信号转导通路激活了肝星状细胞,从而促进肝纤维化的发生发展。Objective To investigate the role ofβ-arrestin1(ARRB1) in liver fibrosis and elucidate the mechanism of hepatic stellate cell activation induced by ARRB1/p38 signaling pathway to promote liver fibrosis. Methods Twelve male C57BJ/6L mice were randomly divided into the control(n = 6) and model groups(n = 6). The liver fibrosis mouse model was established by 20% carbon tetrachloride. In addition, liver tissue samples from patients with liver cirrhosis and healthy controls were collected.Liver fibrosis was assessed by HE and Sirius red staining. The expression levels of ARRB1, p38, pp38, α-SMA and collagen Ⅰwere detected by immunohistochemistry, western blot and quantitative real-time PCR. The human hepatic stellate cell line LX2 was activated by TGF-β cytokine and the expression level of ARRB1 was analyzed. Furthermore, siRNA or plasmid was used to silence or overexpress ARRB1, and p38 specific inhibitor(SB203580) was adopted to reveal the regulatory relationship between ARRB1and p38. Results ARRB1 expression was up-regulated and the activation of p38 signal was strengthened in liver fibrosis tissues(all P < 0.05). TGF-β treatment activated hepatic stellate cells and ARRB1 and p38 signaling in hepatic stellate cell LX2. The upregulation or down-regulation of ARRB1 expression level could correspondingly affect p38 signaling and regulate the activity of hepatic stellate cells, while the change of p38 activity exerted no effect uponthe expression of ARRB1. Conclusion The expression level of ARRB1 is up-regulated in liver fibrosis, which can activate hepatic stellate cells by activating the p38 signaling, thereby promoting the incidence and development of liver fibrosis.

关 键 词：肝纤维化 β-arrestin1 肝星状细胞 P38 

分 类 号：R575.2[医药卫生—消化系统]