| Background:With social development and improvement of people's living standards, the incidence of atherosclerosis(AS) is increasing rapidly in recent years. It is believed that the pathological basis of coronary heart disease(CHD) is vascular endothelial injury and formation of subcutaneous atheromatous plaque. Statins, which is an inhibitor of HMGCR,can effectively lower cholesterol level and has been widely used in patients with AS.Atorvastatin calcium(ATRO) is a kind of fat soluble statin with potent effect. However,with the widely use of ATRO, adverse reactions were found such as liver damage, muscle damage and especially increased levels of transaminase.Although statins can increase the transaminase level, it also plays an essential role in antioxidant and myocardial protection. Statins may be associated with liver damage,however, it is necessary to further study the possible mechanism, which is important to the clinical application. Our previous study found that serum bilirubin level of Plin5 deficient mice was significantly increased. However, the specific role of Plin5 needs more study.Therefore, this study aims to find the possible mechanism of ATRO in bilirubin level and its related factors, the relationship between serum bilirubin level and different doses ofdrugs.Objective:1?To investigate the short-term application of different doses of ATRO on the level of serum bilirubin in patients with CHD, and to study the related factors among elevated bilirubin, transaminase level, and body mass index(BMI). To indentify the main related factor of ATRO-related bilirubin elevation.2?To study the role of Plin5 in ATRO involved process by analyzing the liver fat metabolism and serum bilirubin level of Plin5 knockout mice using ATRO.Methods:Part one:1?264 patients were included according to standard crteria. All of them were patients with CHD and first administrated with ATRD. The patients were divided into 2 groups(20mg/day and 40 mg/day). Bilirubin levels and other biochemical indexes were recorded before and after treatment.2?The relation between BMI, transaminase and serum bilirubin were studied by analyzing the subgroup.Part two:1?Two groups( each = 20) are used: the contrasting group of wild-type(Plin5+/+)mice and the group of Plin5 knockout(Plin5-/-) mice. At the age of 4 weeks, the mice were fed with high fat diet(HFD) for 8 weeks. During this period, the mice were monitored by measuring the weight and blood glucose once each week(blood glucose measurement).From the tenth week, both groups were given 10 mg/kg/d atorvastatin calcium suspension and saline by gavage for 10 days.2 ? The samples of mice blood were measured of blood biochemical indexes of various, such as the weight of the main organs. liver, heart, muscle to do tissue sections.To determine the effect of statins on the main metabolic parameters of Plin5 knockout mice. Western blot detection is implemented by being extracted protein and oxidative stress detection is implemented by being extracted liver tissue.Results:1?AST,ALT,TB,DB were significantly higher in the patients enrolled in this studyafter they took atovastatin calcium(P<0.05), and there was no differences in the level of IB. Furthermore, patients taking 40 mg atorvastatin calcium had higher serum AST,ALT,TB and DB level than patients taking 20 mg(P<0.05). In addition, there was a significant correlation between the levels of TB and the levels of TC in CHD patients after they taking atorvastatin.(Pearson correlation analysis 20 mg group r=0.419, 40 mg group r=0.4875, p<0.0001). However, there was no significant correlation between creatinine,uric acid,triglyceride levels and TB,DB and IB levels.2?The patients were divided into two groups: BMI?24 and BMI>24.AST, ALT and bilirubin were significantly increased(P<0.05) in both groups of patients after taking atorvastatin calcium. However, ALT and TB levels increased much higher in BMI >24group than that in the BMI ? 24group(P<0.05).These results indicated that the level of serum bilirubin was closely related to hepatic fat metabolism after taking atorvastatin calcium.3 ? ATRO reduced the liver weight of Plin5 deficient mice. At the same time,compared with the control group, serum AST,ALT,TB,DB of mice significantly increased after intragastric administration of ATRO. Compared with the wild-type mice, the elevation of serum ALT?AST?TB?DB was more obvious in Plin5 knock-out mice.4?The results of liver tissue oil red O staining showed that ATRO could reduce the number of lipid droplets in the liver cells of wild mice and Plin5 knockout mice. In addition, ATRO could increase the level of 4HN and MD in liver tissue of both wild type and Plin5 knockout mice, and reduce the activity of SOD.5?Western Blot results showed that ATRO could significantly reduce the level of liver Plin5 expression. However, the increase of Plin5 expression in the heart and skeletal muscle was not obvious. At the same time, ATRO could further increase the level of PPAR? and its downstream molecules in Plin5 knockout mice.Conclusion:After clinical analysis of patients taking atorvastatin, we found that ATRO could increase the levels of DB, ALT, TB and AST, which showed a dose dependent effect. Theresults of the relative factors analysis showed that the level of serum bilirubin was significantly correlated with total cholesterol and body mass index. These results indicated that the increase in the level of serum bilirubin might be closely related to the hepatic fat metabolism.ATRO could reduce the Plin5 expression level in the liver. ATRO could also increase the level of serum bilirubin in Plin5 deficient mice, and further activated PPAR? and increase liver ROS levels of Plin5 knockout mouse. These results indicated that ATRO could decrease the expression of Plin5 and activate of PPAR?, which led to the increase of serum bilirubin level and affected hepatic fat metabolism. This study would help us further understand the mechanism of the protective effect of statins, and provide research basis for further clinical application. |
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