title: 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, the BA uptake transporters Na⁺/taurocholate cotransporting polypeptide and organic anion transporting polypeptide 1b2, and the efflux transporter multidrug resistance-associated protein 2 in the liver. Noticeably, atorvastatin suppressed the expression of BA nuclear receptor farnesoid X receptor (FXR) target genes, namely small heterodimer partner (liver) and fibroblast growth factor 15 (ileum). Furthermore, atorvastatin increased the mRNAs of the organic cation uptake transporter 1 and cholesterol efflux transporters Abcg5 and Abcg8 in the liver. 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.
authors.affiliation: Departments of Pharmacology, Toxicology, and Therapeutics University of Kansas Medical Center, Kansas City, KS 66160 Department of Pharmacology, Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin, Heilongjiang Province, People's Republic of China 150081.
authors.forename: Zidong Donna
authors.initials: ZD
authors.lastname: Fu
authors.affiliation: Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160.
authors.forename: Julia Yue
authors.initials: JY
authors.lastname: Cui
authors.affiliation: Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160.
authors.forename: Curtis D
authors.initials: CD
authors.lastname: Klaassen
mesh_terms: D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000069059:Atorvastatin; D001647:Bile Acids and Salts / Q000097:blood / Q000378:metabolism; D053493:Cholestanetriol 26-Monooxygenase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D065693:Cytochrome P-450 Enzyme Inducers / Q000494:pharmacology*; D004764:Enterohepatic Circulation / Q000187:drug effects; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007082:Ileum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008074:Lipoproteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008810:Mice, Inbred C57BL; D029363:Organic Anion Transporters, Sodium-Dependent / Q000819:agonists / Q000737:chemistry / Q000235:genetics; D029362:Organic Anion Transporters, Sodium-Independent / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D027981:Symporters / Q000819:agonists / Q000737:chemistry / Q000235:genetics
chemical_list: C462600:ABCG5 protein, mouse; C462601:ABCG8 protein, mouse; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts; D065693:Cytochrome P-450 Enzyme Inducers; C496283:Fxr1h protein, mouse; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008074:Lipoproteins; D027381:Liver-Specific Organic Anion Transporter 1; D029363:Organic Anion Transporters, Sodium-Dependent; D029362:Organic Anion Transporters, Sodium-Independent; D011758:Pyrroles; D016601:RNA-Binding Proteins; C498887:Slco1b2 protein, mouse; D027981:Symporters; C071908:sodium-bile acid cotransporter; D000069059:Atorvastatin; D002790:Cholesterol 7-alpha-Hydroxylase; C502772:Cyp7a1 protein, mouse; D053493:Cholestanetriol 26-Monooxygenase; C506832:Cyp27a1 protein, mouse
keywords: cholesterol 7α-hydroxylase; farnesoid X receptor signaling; ultra-performance liquid chromatography-tandem mass spectrometry