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

Abstract

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.

Circadian Clock Gene Expression and Drug/Toxicant Interactions as Novel Targets of Chronopharmacology and Chronotoxicology

“…Since Cyp7a1 is a clock-driven gene, its effects on circadian clock gene expression were also examined. Atorvastatin increased the expression of Bmal1, Npas2, decreased the expression of Per2, Per3, Dbp, and Tef, but had no effect on Cry1 and Nr1d1 [56]. The similar effects on the circadian clock gene expression were also observed when atorvastatin was given at the low dose (10 mg/kg) but for a longer period of 90 days, although to a less extent [57].…”

Atorvastatin Modulates Bile Acid Homeostasis in Mice with Diet-Induced Nonalcoholic Steatohepatitis

“…The majority of available studies indicate that statins increase Cyp7a1 mRNA expression in rodents [ 19 , 20 , 44 , 46 ], likely due to the decreased FXR signaling [ 20 ]. It was anticipated that increased expression of Cyp7a1 mRNA compensates for the reduced synthesis of FXR agonistic BA such as CA and DCA due to the statin-induced blockade of cholesterol synthesis [ 20 ].…”

“…The cause of such diversity may be the variability of dosage schedules tested in different species. Indeed, an analysis of dose-dependency uncovered a culminating effect of atorvastatin on the mRNA levels of Bsep, Ntcp, Cyp7a1, and Shp at the dose of 30 mg/kg, with its attenuation at 100 mg/kg [ 46 ]. Thus, our study presents the mid-term effects of statins given at a submaximal effective dosage.…”

RNA-Seq Profiling of Intestinal Expression of Xenobiotic Processing Genes in Germ-Free Mice

“…Intestinal bacteria are responsible for producing secondary bile acids from primary bile acids through deconjugation, dehydroxylation, epimerization, and oxidation Wahlstrom et al, 2016;Li et al, 2017). It is known that GF mice have diminished secondary bile acids but more total and conjugated bile acids in the intestine (Sayin et al, 2013;Selwyn et al, 2015a).…”