Atorvastatin Alters The Expression Of Genes Related To Bile Acid Metabolism And Circadian Clock In Livers Of Mice

Objection: Atorvastatin is a HMG-Co A reductase inhibitor(HMGCR) used for hyperlipidemia. In clinic, atorvastatin is generally safe, but may induce cholestasis. The present study aimed to examine the time-course and dose-response of atorvastatin in the liver focusing on gene expression related to bile acid metabolism and homeostasis, as well as the expression of circadian clock genes in mice.Methods: In 30 d experiment, adult male mice were given atorvastatin(10, 30, and 100 mg/kg, po) daily for 30d; and in 90 d experiment, mice were given atorvastatin at clinic dose(10 mg/kg, po) daily for 90 d. At the end of experiment, blood biochemistry, histopathology, and gene expression were examined.Result: In 30 d experiment, atorvastatin did not affect animal body weight gain, liver weights and serum enzyme activities. Histologically, the high dose of atorvastatin produced scattered hepatocyte swollen, 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, Ost-α, and Ost-β. 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.Administration of atorvastatin for 90 d at 10 mg/kg did not show overt liver injury. The expression of stress-associated genes showed no significant changes. Atorvastatin slightly increased the expression of Cyp7a1, FXR and SHP along with the increased expression of Bmal1 and Clock. However, it had no significant effects on Cry1, Per2, Dbp and Nr1d1. These results are in agreement with the 30 d experiment, but the effects were mild.Conclusion:Administrate of atorvastatin at 10 times of clinical dose for 30 d and at clinical dose for 90 d showed no significant hepatotoxicity, but the high dose of atorvastatin was associated with mild inflammation, and all doses could affect bile acid metabolism and circadian clock-related genes in livers of mice. The effects of clinical dose of atorvastatin for 90 d are mild than 10-fold of clinical dose for 30 d.