中性粒细胞弹性蛋白酶抑制剂Sivelestat在非酒精性脂肪性肝炎相关肝细胞癌的作用机制  

The mechanism of neutrophil elastase inhibitor Sivelestat in non-alcoholic steatohepatitis related hepatocellular carcinoma

作　　者：罗燕[1] 庄振杰[1] 沈璐 顾佳萍 王丽燕 徐佳丽[2] Luo Yan

机构地区：[1]杭州师范大学附属医院,310015 [2]杭州师范大学,311121 [3]浙江中医药大学,310053

出　　处：《浙江临床医学》2021年第10期1391-1393,1396,共4页Zhejiang Clinical Medical Journal

基　　金：国家自然科学基金资助项目(81570524);浙江省自然科学基金资助项目(LQ17H070002);杭州市科技发展计划项目(20170533B42)。

摘　　要：目的探讨中性粒细胞弹性蛋白酶抑制剂Sivelestat在非酒精性脂肪性肝炎相关肝细胞癌(NASH-HCC)中的作用。方法采用高脂高胆固醇饮食诱导联合皮下注射链脲佐菌素的方法构建C57BL/6J小鼠NASH-HCC模型,60只雄性小鼠随机分为普通饮食(对照)组、高脂高胆固醇饮食(模型)组、Sivelestat抑制剂(干预)组。于第12周、16周收集血清和肝组织进行血生化测定及病理分析,HE染色观察Sivelestat干预对NASH-HCC小鼠肝脏病理的影响。荧光定量PCR检测脂质合成相关基因FASN、SCD1、SREBP1c的表达情况c结果Sivekstat可以明显减轻模型组小鼠的肝重、肝指数、TC、HDL、LDL及FPG水平。Sivelestat对模型小鼠肝酶ALT、AST有减轻作用,可显著降低16周模型组小鼠ALT水平。HE染色显示Sivelestat干预组小鼠12周、16周脂肪变较同周龄模型组明显减轻。Siveksut干预12周可减轻脂肪变和小叶内炎症评分,总NAS积分也较模型组降低,但差异不显著;Sivelestat干预16周,脂肪变水平有所减轻,而炎症水平略有升高;总NAS积分与模型组比较,无统计学差异。脂质合成相关基因检测显示,模型组小鼠肝脏脂肪酸合酶(FASN)、硬脂酰辅酶A去饱和酶(SCD1)、固醇调节元件结合蛋白1c(SREBP1c)表达显著升高,Sivelestat干预至16周可显著降低脂质合成相关基因的表达。结论Sivelestat可减轻NASH-HCC小鼠肝脏脂肪变,减轻早期炎症,对NASH-HCC的发生发展有一定的抑制作用。Objective To investigate the role of neutrophil clastase inhibitor Sivelestat in non-alcoholic steatohepatitis related hepatocellular carcinoma.Methods NASH-HCC model of C57BL/6J mice was established by high fat and high cholesterol diet combined with subcutaneous injection of streptozotocin.Sixty male mice were randomly divided into nonnal diet group(control group),high fat and high cholesterol diet group(model group)and Sivelestat inhibitor group(intervention group).Serum and liver rissues were collected at 12th week and 16th week for blood biochemical determination and pathological analysis,and liver HE staining was performed to observe the effect of Sivelestat intervention on liver pathology of NASH-HCC mice.The expressions of lipid synthesis related genes FASN,SCD1 and SREBP1c were detected by fluorescence quantitative PCR.Results Sivelestat could significantly reduce liver weight,liver index,TC,HDL,LDL and FPG levels in model group.Sivelestat could reduce the liver enzyme ALT and AST in model mice,and significantly reduce the ALT level in the 16-week model group.HE staining showed that steatosis was significantly reduced in Sivelestat intervention group at 12th week and 16th week compared with model group of the same week of age.Sivelestat intervention reduced steatosis and intra-lobular inflammation scores at 12th week,and total NAS scores were also lower than those in the model group,but the difference was not significant.Sixteen weeks of Sivelestat intervention resulted in a reduction in steatosis and a slight increase in inflammation.There was no staristically significant difference in total NAS score between intervention group and model group.Detection of genes related to lipid synthesis showed that the expressions of fatty acid synthase(FASN),stearyl coenzyme A desaturase(SCD1)and sterol regulatory element binding protein 1c(SREBP1c)in liver of mice in model group were significandy increased,and the expression of genes related to lipid synthesis could be significantly decreased after Sivelestat interv

关 键 词：中性粒细胞弹性蛋白酶 非酒精性脂肪性肝炎相关肝细胞癌 巨噬细胞 

分 类 号：R28[医药卫生—中药学]