title: Bile acid and sterol metabolism with combined HMG-CoA reductase and PCSK9 suppression.
abstract: Proprotein convertase subtilisin-kexin-9 (PCSK9) inhibition markedly augments the LDL lowering action of statins. The combination is being evaluated for long-term effects on atherosclerotic disease outcomes. However, effects of combined treatment on hepatic cholesterol and bile acid metabolism have not yet been reported. To study this, PCSK9-Y119X mutant (knockout) and wild-type mice were treated with or without atorvastatin for 12 weeks. Atorvastatin progressively lowered plasma LDL in each group, but no differences in liver cholesterol, cholesterol ester, or total bile acid concentrations, or in plasma total bile acid levels were seen. In contrast, atorvastatin increased fecal total bile acids (≈ 2-fold, P < 0.01) and cholesterol concentrations (≈ 3-fold, P < 0.01) versus controls for both PCSK9-Y119X and wild-type mice. All 14 individual bile acids resolved by LC-MS, including primary, secondary, and conjugated species, reflected similar increases. Expression of key liver bile acid synthesis genes CYP7A1 and CYP8B1 were ≈ 2.5-fold higher with atorvastatin in both strains, but mRNA for liver bile acid export and reuptake transporters and conjugating enzymes were not unaffected. The data suggest that hepatocyte cholesterol and bile acid homeostasis is maintained with combined PCSK9 and HMG-CoA reductase inhibition through efficient liver enzymatic conversion of LDL-derived cholesterol into bile acids and excretion of both, with undisturbed enterohepatic recycling.
authors.affiliation: Cardiovascular Discovery Biology, Bristol-Myers Squibb Pharmaceutical Research and Development, Pennington, NJ 08534, USA. rex.parker@bms.com
authors.forename: Rex A
authors.initials: RA
authors.lastname: Parker
authors.forename: Ricardo
authors.initials: R
authors.lastname: Garcia
authors.forename: Carol S
authors.initials: CS
authors.lastname: Ryan
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Liu
authors.forename: Petia
authors.initials: P
authors.lastname: Shipkova
authors.forename: Valentin
authors.initials: V
authors.lastname: Livanov
authors.forename: Pritesh
authors.initials: P
authors.lastname: Patel
authors.forename: Siew P
authors.initials: SP
authors.lastname: Ho
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D004347:Drug Interactions; D005243:Feces / Q000737:chemistry; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors*; D011480:Protease Inhibitors / Q000494:pharmacology*; D012697:Serine Endopeptidases
chemical_list: D001647:Bile Acids and Salts; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011480:Protease Inhibitors; D002784:Cholesterol; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
keywords: 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors; CYP7A1; N-ethyl N-nitrosourea mutagenesis; bile acid transporter; cholestasis; low desnsity lipoprotein receptor; proprotein convertase subtilisin-kexin-9 inhibitors; statins