Study On The Mechanism Of Bile Acid Metabolism After Atorvastatin-Induced Liver Injury

Objective: Objective: With the improvement of economic level and people’s quality of life,the incidence of cardiovascular diseases is increasing,and the prevention and treatment of cardiovascular diseases is becoming more and more important.Statins have been shown to play a key and important role in the prevention and treatment of cardiovascular disease,but with the increasing use of statins has come associated post-use problems.The mechanism of liver-related damage caused by its administration is not very clear at present.By establishing a mouse model of liver injury induced by atorvastatin,we explored and verified the mechanism related to the effect of atorvastatin on bile acid metabolism,hoping to reveal the role of statins in bile acid metabolism and explore the relationship between statins and bile acid metabolism related pathways.To provide clinical treatment strategies for patients with liver injury caused by statin use.Methods: Forty SPF male C57BL/6 mice were randomly divided into control group(group A),atorvastatin low-dose group(10mg,group B),intermediate-dose group(20mg,group C)and high-dose group(30mg,group D),with 10 mice in each group.After 30 days of intragastric administration,the liver weight index of each group was compared.HE staining was performed on liver tissues,and then orbital blood was collected to detect and compare the expressions of total bile acid(TBA),endotoxin(ET),aspartate aminotransferase(AST)and alanine aminotransferase(ALT)in each group.Bile acid metabolism related gene Farnesol X receptor(FXR)gene and multi-drug resistance related protein 2(MRP2)expression were detected in liver tissues.Results: Compared with the control group,the changes of body weight and liver weight index in the other 3 groups had no statistical significance(P > 0.05).After HE staining in each group,the liver tissue cells in the atorvastatin high-dose group showed slight bulge-like changes,scattered inflammatory cell infiltration and feather-like degeneration(Figure 1D).Compared with the control group,atorvastatin dose was positively correlated with the increase of blood TBA,ET,AST and ALT.Compared with the control group,TBA,ET,AST and ALT in atorvastatin high-dose group were significantly increased and the difference was statistically significant(Table 2,P<0.05).Compared with the control group,the expression levels of FXR and MRP2 in atorvastatin medium-dose and high-dose groups decreased,and the difference was statistically significant(Table 3,P <0.05).Conclusion: Our results showed that gradually increasing the dosage of atorvastatin can induce increased expression of total bile acid in mice,which may be related to the changes of FXR and MRP genes related to downstream bile acid metabolism induced by atorvastatin.Such abnormal bile acid metabolism caused by high dose administration may be the main cause of liver toxicity of atorvastatin.However,in general,the use of oral drug doses has shown relative safety.