FGF1通过抑制内质网应激和自噬途径保护对乙酰氨基酚诱导的小鼠肝损伤

Fibroblast growth factor 1 protects acetaminophe-induced liver injury in mice by inhibiting endoplasmic reticulum stress and autophagy

目的探讨成纤维细胞生长因子1(FGF1)对对乙酰氨基酚(APAP)诱导的小鼠肝损伤的保护作用以及相应的机制。方法将30只雄性C57BL/6小鼠随机分为APAP+FGF1组、APAP组和正常对照组3组,每组10只;腹腔注射500mg/kgAPAP诱导小鼠急性肝损伤,24h后处死小鼠;收集3组小鼠血浆和肝脏组织。ELISA法检测血浆ALT水平,HE染色法观察肝脏组织形态学改变,Western blot法检测内质网应激信号通路相关蛋白GRP78、ATF6、PDI、XBP-1、Caspase-3和CHOP表达,以及自噬信号通路相关蛋白ATG7、Beclin-1、ATG5、LC-3I/II表达;免疫荧光染色法检测GRP78、ATG7、LC-3蛋白表达。结果与正常对照组比较,APAP组ALT水平上升(P<0.05),肝细胞损伤及肝索内出血更为严重,肝组织内质网应激及自噬相关蛋白表达均明显增加(均P<0.05);与APAP组比较,APAP+FGF1组ALT水平明显下降(P<0.05),肝细胞损伤程度减轻,肝组织内质网应激及自噬相关蛋白表达均明显下降(均P<0.05)。结论内质网应激和自噬途径在APAP诱导的小鼠肝损伤过程中起到重要作用,且FGF1通过抑制内质网应激、自噬途径保护APAP诱导的小鼠肝损伤。

Objective To investigate the protective effect of fibroblast growth factor 1(FGF1) on liver injury induced by paracetamol(APAP) in mice and its mechanism. Methods Thirty male C57 BL/6 mice were randomly divided into normal control group(control group), APAP treatment group(APAP group), APAP + FGF1 treatment group(APAP + FGF1 group) with 10 mice in each group.Acute liver injury was induced by intraperitoneal injection of 500 mg/kg APAP in mice. After 24 h, mice were sacrificed, plasma and liver tissue samples were collected from three groups of mice. The plasma ALT level was measured by ELISA kit. The histomorphological changes of liver were observed by light microscopy with HE staining. The expressions of GRP78, ATF6, PDI, XBP-1, Caspase-3 and CHOP as well as the expressions of autophagy-related proteins ATG5, ATG7, Beclin-1 and LC-3 I/II were detected by Western blot. The protein expressions of GRP78, ATG7 and LC-3 in liver tissue were detected by immunofluorescence staining. Results Compared with the control group, ALT level in APAP group increased significantly(P<0.05), and hepatocyte injury and intrahepatic hemorrhage in APAP group were more serious,and the expressions of endoplasmic reticulum stress and autophagy-related proteins in liver tissue were significantly increased(all P<0.05).After FGF1 treatment, compared with APAP group, the ALT level in APAP + FGF1 group decreased significantly(P<0.05), and the degree of hepatocyte injury decreased, and the expressions of endoplasmic reticulum stress and autophagy-related proteins in liver tissue decreased significantly(P<0.05). Conclusion Endoplasmic reticulum stress and autophagy pathway play an important role in APAP-induced liver injury of mice. FGF1 protects APAP-induced liver injury in mice by inhibiting endoplasmic reticulum stress and autophagy.