Research On Effects Of Clusterin On The Development Of Chronic Liver Fibrosis In Mice

There is a large number of liver patients in China.Due to the limited selection of current liver disease treatment strategies and liver fibrosis may continue to develop into liver cirrhosis or even liver cancer,it seriously endangers the lives and health of the people.This urges researchers to realize the comprehensiveness of the occurrence and development of liver fibrosis and the specificity of related pathway factors as soon as possible.This subject is based on the currently known processes and mechanisms of liver fibrosis,focusing on emerging ways to improve liver fibrosis,and found that Clusterin(CLU)protein has a certain role in liver fibrosis.Through two aspects,the expression characteristics and localization of CLU protein are analyzed.And the occurrence of liver fibrosis in CLU-/-mice induced by drugs,and the specific expression type,location and effect of CLU in the liver are preliminarily described.Chronic liver injury is caused by exposure to chemically toxic drugs,alcohol abuse,viral infections,autoimmune diseases and other factors,which cause liver inflammation activation and oxidative stress,causing a large number of liver myofibroblasts to activate and form extracellular matrix deposition.And most of them are accompanied by inflammatory cell infiltration,causing the liver to form a fibrous scar structure,which affects the physiological function of the liver,that is,after the fibrogenesis stage,if the damage persists,it will slowly progress from liver fibrosis to cirrhosis,and even liver cancer.Regarding the treatment of liver disease,the primary task is to remove the cause,but at present,only the use of antiviral drugs to treat virally infected liver disease has achieved good clinical results,and there are no effective clinical treatments for the other.This is mainly because the understanding of the microenvironment of liver fibrosis and related proteins or factors is not deep enough.The study of the role of specific molecules and cells in the environment of liver fibrosis and the analysis of the pathways involved will provide important treatment for chronic liver injury significance.Clusterin(CLU)is a secreted glycoprotein that forms a heterodimer from a chain and βchain;also known as apolipoprotein J,it is widely present in human body fluids and tissues,and a variety of biological functions have been reported.Protein homeostasis,promote cell survival,etc.CLU is also involved in lung injury repair,lipid metabolism,renal fibrosis,and amyloid dissolution in Alzheimer’s disease.In our previous experimental results,we can see that CLU is lowly expressed in normal liver tissues,while it is highly expressed in CCL4induced liver injury tissues,and it is concentrated in the fibrotic injury area.This more reveals the relationship between CLU and chronic injury and fibrosis.Functional relevance.It is currently believed that the process of liver fibrosis involves the release of factors from hepatocyte degeneration and necrosis,which activates inflammatory cells to release proinflammatory factors,and promotes the activation of hepatic stellate cells and other fibroblasts to produce extracellular matrix to form liver fibrosis.It can be seen that the reduction of liver cell death,the release of inflammatory factors,and the activation of fibroblasts play an important role in inhibiting fibrosis and improving liver structure by regulating the three stages.So does CLU protein affect the development of liver fibrosis?In which protein form,is it by changing its effect on liver cells or the way it regulates myofibroblasts?Therefore,in order to further clarify the relationship between CLU and chronic liver injury,we conducted the following experimental studies:(1)First,the expression position of CLU in mice was identified,and the hepatic parenchymal cells expressed in individual scattered spots in the normal liver.The cytoplasm of individual hepatocytes in the central venous area and individual surrounding hepatocytes and bile duct cells in the portal area.By increasing the model of chronic liver injury,cholestatic liver fibrosis,non-alcoholic fatty liver disease induced by high-fat diet,and CCL4-induced liver fibrosis,the expression of CLU in damaged liver tissue was detected,and the results showed that CLU is in liver fiber The expression of CLU is the highest in the fibrotic model,and CLU is low in other fatty liver models,and the expression position is correlated with the fibrotic injury area,revealing that CLU is related to the expression level of fibrosis.And through staining,it was found that CLU was highly expressed in the injured area.The co-localization test with hepatocytes,cholangiocytic cells and stellate cells showed that CLU protein increased from cholangiocytic cells after increased liver injury,and was highly expressed in the liver around the injured area.Among cells,it is not expressed in stellate cells,revealing that CLU exhibits a feedback increase after liver injury,indicating its important role in liver fibrosis.(2)Comparison and identification analysis of phenotypic characteristics of normal mice and clusterin knockout mice.The successful establishment of the mouse model was determined at the genome level and proteome level,and the phenotypic differences were compared.The results showed that the clusterin knockout mice It has no effect on the normal growth of mice.(3)Establish a liver fibrosis model of clusterin knockout mice.Compared with wild-type mice treated with the same conditions,through collagen staining and Western Blot analysis,knockout mice are within 2 weeks at the same time,it showed obvious collagen deposition,and fibrosis occurred more rapidly than wild-type mice,and the signs of fibrosis were more serious in the same period.It shows that CLU plays an important role in the protection of liver injury in mice.Conclusion:During the occurrence and development of liver fibrosis,CLU secreted protein exhibits high feedback expression,and a large number of them are expressed in bile duct cells and hepatocytes in the area of liver injury.Through the establishment of liver fibrosis model of Clu-/-mice,Clu-/-mice develop liver fibrosis more rapidly and severely,indicating that CLU has an inhibitory effect on the development of liver fibrosis.