Atorvastatin alters the expression of genes related to bile acid metabolism and circadian clock in livers of mice

PeerJ

article

Wen-Kai Li¹  Huan Li¹  Yuan-Fu Lu¹  Ying-Ying Li¹  Zidong Donna Fu³  Jie Liu¹ 

[1] Key Lab for Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical College;Department of Pharmacology, Shanghai University of Chinese Traditional Medicine;Department of Environmental and Occupational Health Sciences, University of Washington

关键词: Cholestasis;    Atorvastatin;    Bile acid transporters;    Cyp7a1;    Clock gene expression;    Mouse liver;   

DOI  :  10.7717/peerj.3348

学科分类：社会科学、人文和艺术（综合）

来源: Inra

【 摘 要 】

AimAtorvastatin is a HMG-CoA reductase inhibitor used for hyperlipidemia. Atorvastatin is generally safe but may induce cholestasis. The present study aimed to examine the effects of atorvastatin on hepatic gene expression related to bile acid metabolism and homeostasis, as well as the expression of circadian clock genes in livers of mice.MethodsAdult male mice were given atorvastatin (10, 30, and 100 mg/kg, po) daily for 30 days, and blood biochemistry, histopathology, and gene expression were examined.ResultsRepeated administration of atorvastatin did not affect animal body weight gain or liver weights. Serum enzyme activities were in the normal range. Histologically, the high dose of atorvastatin produced scattered swollen hepatocytes, foci of feathery-like degeneration, together with increased expression of Egr-1 and metallothionein-1. Atorvastatin increased the expression of Cyp7a1 in the liver, along with FXR and SHP. In contract, atorvastatin decreased the expression of bile acid transporters Ntcp, Bsep, Ostα, and Ostβ. The most dramatic change was the 30-fold induction of Cyp7a1. Because Cyp7a1 is a circadian clock-controlled gene, we further examined the effect of atorvastatin on clock gene expression. Atorvastatin increased the expression of clock core master genes Bmal1 and Npas2, decreased the expression of clock feedback genes Per2, Per3, and the clock targeted genes Dbp and Tef, whereas it had no effect on Cry1 and Nr1d1 expression.ConclusionRepeated administration of atorvastatin affects bile acid metabolism and markedly increases the expression of the bile acid synthesis rate-limiting enzyme gene Cyp7a1, together with alterations in the expression of circadian clock genes.

【 授权许可】

CC BY