Atorvastatin induces bile acid-synthetic enzyme Cyp7a1 by suppressing FXR signaling in both liver and intestine in mice.
Abstract
Statins
are effective cholesterol-lowering drugs to treat CVDs. Bile acids
(BAs), the end products of cholesterol metabolism in the liver, are
important nutrient and energy regulators. The present study aims to
investigate how statins affect BA homeostasis in the enterohepatic
circulation.
Male C57BL/6 mice were treated with atorvastatin (100 mg/kg/day po) for 1 week, followed by BA profiling by ultra-performance LC-MS/MS.
Atorvastatin decreased BA pool size, mainly due to less BA in the intestine. Surprisingly, atorvastatin did not alter total BAs in the serum or liver.
Atorvastatin increased the ratio of 12α-OH/non12α-OH BAs.
Atorvastatin increased the mRNAs of the BA-synthetic enzymes
cholesterol 7α-hydroxylase (Cyp7a1) (over 10-fold) and
cytochrome P450 27a1, (Cyp27a1; Sterol 27-hydroxylase)
the BA uptake transporters:
Na⁺/taurocholate cotransporting polypeptide (Ntcp)
and organic anion transporting polypeptide 1b2, (Oatp 1)
and the efflux transporter multidrug resistance-associated protein 2 (Abcc2) ) in the liver.
Noticeably, atorvastatin suppressed the expression of BA nuclear receptor farnesoid X receptor (FXR) target genes,
namely small heterodimer partner (liver) (Shp, Short heterodimer partner)
and fibroblast growth factor 15 (ileum). (Fgf15)
Furthermore, atorvastatin increased
the mRNAs of the organic cation uptake transporter 1
and cholesterol efflux transporters Abcg5, ( ATP-binding cassette subfamily G member 5)
and Abcg8 in the liver ( ATP-binding cassette subfamily G member 8).
The increased expression of BA-synthetic enzymes and BA transporters appear to be a compensatory response to maintain BA homeostasis after atorvastatin treatment.
The Cyp7a1 induction by atorvastatin appears to be due to suppressed FXR signaling in both the liver and intestine.
Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.
Male C57BL/6 mice were treated with atorvastatin (100 mg/kg/day po) for 1 week, followed by BA profiling by ultra-performance LC-MS/MS.
Atorvastatin decreased BA pool size, mainly due to less BA in the intestine. Surprisingly, atorvastatin did not alter total BAs in the serum or liver.
Atorvastatin increased the ratio of 12α-OH/non12α-OH BAs.
Atorvastatin increased the mRNAs of the BA-synthetic enzymes
cholesterol 7α-hydroxylase (Cyp7a1) (over 10-fold) and
cytochrome P450 27a1, (Cyp27a1; Sterol 27-hydroxylase)
the BA uptake transporters:
Na⁺/taurocholate cotransporting polypeptide (Ntcp)
and organic anion transporting polypeptide 1b2, (Oatp 1)
and the efflux transporter multidrug resistance-associated protein 2 (Abcc2) ) in the liver.
Noticeably, atorvastatin suppressed the expression of BA nuclear receptor farnesoid X receptor (FXR) target genes,
namely small heterodimer partner (liver) (Shp, Short heterodimer partner)
and fibroblast growth factor 15 (ileum). (Fgf15)
Furthermore, atorvastatin increased
the mRNAs of the organic cation uptake transporter 1
and cholesterol efflux transporters Abcg5, ( ATP-binding cassette subfamily G member 5)
and Abcg8 in the liver ( ATP-binding cassette subfamily G member 8).
The increased expression of BA-synthetic enzymes and BA transporters appear to be a compensatory response to maintain BA homeostasis after atorvastatin treatment.
The Cyp7a1 induction by atorvastatin appears to be due to suppressed FXR signaling in both the liver and intestine.
Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.
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