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.
Highlights
Proprotein convertase subtilisin-kexin-9 (PCSK9) inhibition markedly augments the LDL lowering action of statins
In initial studies of the mutant mice, very low levels of PCSK9 mRNA for homozygous Y119X mice and ف50% lower PCSK9 mRNA for the heterozygotes were measured by RT-PCR compared with wild type, suggesting nonsense mediated decay of the point-mutant PCSK9 mRNA
Liver LDL receptor (LDLR) protein levels were increased ف2-fold in the heterozygous and 3-fold in the homozygous mutants compared with wild type, and plasma low density lipoprotein cholesterol (LDL-C) was ف50% lower in the heterozygous and ف80% lower in the Y119X homozygous mice compared with wildtype controls (Fig. 1, right panel)
Summary
Proprotein convertase subtilisin-kexin-9 (PCSK9) inhibition markedly augments the LDL lowering action of statins. Effects of combined treatment on hepatic cholesterol and bile acid metabolism have not yet been reported. Evaluation of PCSK9 inhibitors in combination with statins is important to understand the full potential of this new class of low density lipoprotein cholesterol (LDL-C) lowering agents. Both statins and PCSK9 inhibitors lower circulating LDL-C levels by increasing LDL receptor (LDLR) activity primarily in liver. The effects of PCSK9 suppression, in the presence and absence of statins, on bile acid metabolism have not been previously reported. The present study was conducted to analyze the pharmacological effects of statins combined with PCSK9 suppression on bile acid and cholesterol balance and gene regulation in a mouse model.
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