Experimental Study On The Pathogenesis And Therapy Of Nonalcoholic Steatohepatitis

Objective:The morbidity of nonalcoholic steatohepatitis is rising.It can progress to hepatic fibrosis, hepatic cirrhosis and other hepatic final stage disease.But its pathogenesis is not distinct,and there is no effective therapeutic tool.In this investigation,we established NASH model of rats by high-fat and high-cholesterol diet。We detected serum insulin level ,serum TNFαlevel,liver constitution homogenate MDA level and SOD activity.In addition,we gave intervention therapy to the rats by insulin sensitiver .In this investigation we tried to explore the following viewpoint.(1) To observe the level of insulin resistance in every stage of NASH model.( 2)To investigate the relationship between TNF-α, oxygen stress/lipid peroxidation and NASH. (3) To investigate the role of insulin sensitiver in formation of NASH. This investigation can help to know the pathogenesis of NASH and instruct clinical therapeuticsMethods:50 rats were divided into 5 groups at random after fed with normal diet for 7 days.Control group I(n=10) were fed with normal diet .Model group I(n=10) and model groupII(n=10) were fed with high-fat and high-cholesterol diet which consisting of the normal diet,13% lard and 2%cholesterol. Administration group I(n=10) and administration model groupII(n=10) were given insulin sensitizer pioglitazone orally while fed with high-fat and high-cholesterol diet.All the rats were put to death after 4 or 9 weeks. Body weight, body length,liver weight , transaminase level, blood glucose,triglyceride,cholesteral,free fatty acid ,insulin level and liver histology were detected. Serum insulin level were detected by radio-immunity technique and serum TNFαlevel were detected by ELISA.Results: 1.After 9 weeks, the model group shew to be abdomen-form obesity, developed lipid metabolism disorder and insulin resistance.The level of serum TNFαwas greater than the control group. The level of ALT and AST shew no significant difference. There was no significant difference between the two group of the level of liver constitution homogenate MDA level and SOD activity.And the livers presented the pathology of hepatocyte steatosis. Every marker of Administration group rats was improved. The liver constitution was normal. 2. After 14 weeks, the level of serum TNFα,lipid metabolism disorder and insulin resistance of the model group shew no progress.The level of ALT and AST was greater than the control group. The level of liver constitution homogenate MDA level increased and SOD activity decreased significantly. Hepatocyte steatosis developed and liver presented the pathology of inflammation cell infiltration. The level of serum TNFα,lipid metabolism disorder and insulin resistance of the administration group rats was improved. And there was no improvement of liver inflammation cell infiltration.Conclusion: 1. Long-term high-fat and high-cholesterol diet can create rat NASH model.There is significant pathology development and pathology staging in this model.2. Insulin resistance plays a key role in the formation of hepatocyte steatosis,but plays no capital role in the formation of liver inflammation cell infiltration.3. Insulin sensitizer pioglitazone can improve hepatocyte steatosis,but has no effect on the formation of liver inflammation cell infiltration.4. Oxygen stress/lipid peroxidation may play an important role in formation of liver inflammation cell infiltration.5. TNFαmay play a role in the formation of NASH by inducing inflammatory reaction and insulin resistance.