P38丝裂原活化蛋白激酶在大鼠非酒精性脂肪肝中的作用

Effects of p38 mitogen-activated protein kinase in rats with nonalcoholic fatty liver disease

目的:观察P38丝裂原活化蛋白激酶(p38 mitogen activated protein kinase,P38MAPK)在大鼠非酒精性脂肪肝(nonalcoholic fatty liver disease,NAFLD)中的表达以及对炎症反应的影响,探讨P38MAPK信号转导通路在NAFLD中的作用。方法:清洁级成年雄性SD大鼠36只,随机分为对照组、高糖模型组和SB203580干预组,每组12只。高糖模型组大鼠经高糖饮食12周造成非酒精性脂肪性肝炎(nonalcoholic steatohepatitis,NASH)模型;SB203580干预组大鼠在给予高糖饮食的同时并每周腹腔注射1次SB203580;12周后处死,留取标本。观察各组肝组织病理学形态,测定血清生化、肝指数、胰岛素抵抗和肝匀浆中炎症因子的含量,免疫印迹法测定肝中p38MAPK、p-p38MAPK的表达。结果:与对照组比较,高糖模型组肝组织病理学显示肝脂肪变性明显,血清中丙氨酸氨基转移酶(alanine aminotransferase,ALT)、天门冬氨酸氨基转移酶(aspertate aminotransferase,AST)、葡萄糖(glucose,Glu)、胆固醇(cholesterol,CHO)、甘油酯(triglyceride,TG)明显升高,肝指数、胰岛素抵抗评估和肝匀浆中肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)和白介素(Interleukin,IL)-6均明显升高;SB203580干预组上述指标较高糖模型组明显减轻。与对照组比较,高糖模型组大鼠肝组织P-P38MAPK表达明显增加;与高糖模型组比较,SB203580干预组PP38MAPK表达明显降低。各组大鼠P38MAPK表达无统计学意义。结论:P38MAPK信号转导通路参与了大鼠NAFLD中炎症因子的调控,在NASH中起着重要作用,对P38MAPK的抑制可成为干预NAFLD的潜在有效手段。

Objective：To observe the influence of p38 mitogen-activated protein kinase（P38MAPK）signal transduction pathway on the inflammatory reaction and to explore the role of P38 MAPK in nonalcoholic fatty liver disease（NAFLD）. Methods：Totally 36 healthy adult male SD rats were randomly divided into three equal groups：normal control group,high sugar model group and SB203580 pretreatment group. Rats in high sugar model group were administered with high-carbohydrate diet for 12 weeks;rats in SB203580 group was administered with high-carbohydrate diet for 12 weeks and injected via abdominal cavity weekly. At the 12 weeks,rats were sacrificed,and pathological changes of the liver tissue were examined with light microscope. Serum biochemistry,liver index,insulin resistance and inflammatory factor expression levels of liver homogenate were examined. P38 MAPK and phospho-p38MAPK（P-P38MAPK）expression condition were determined by Western blot. Results：Compared with those in normal control group,the obvious hepatic steatosis was observed in high sugar model group and alanine aminotransferase,aspertate aminotransferase,glucose,cholesterol,triglyceride in the serum,liver index,insulin resistance and tumor necrosis factor-α,interleukin-6 of liver homogenate were increased obviously in high sugar model group. Compared with those in high sugar model group,those indexes were improved in SB203580 pretreated group. The expression levels of P-P38 MAPK in liver tissues were significantly higher in high sugar model group than in control group and the expression of p-p38 MAPK were reduced significantly in SB203580-group than in high sugar model group. There was no difference in P38 MAPK expression among three groups. Conclusion：P38MAPK signal transaction path participates in cytokines releasion process and plays an important role in NASH. Inhibition of P38 MAPK activity has the potential as an effective therapeutic strategy in interventions of NAFLD.