Decreased APOE-containing HDL subfractions and cholesterol efflux capacity of serum in mice lacking Pcsk9

Abstract

BackgroundStudies in animals showed that PCSK9 is involved in HDL metabolism. We investigated the molecular mechanism by which PCSK9 regulates HDL cholesterol concentration and also whether Pcsk9 inactivation might affect cholesterol efflux capacity of serum and atherosclerotic fatty streak volume.MethodsMass spectrometry and western blot were used to analyze the level of apolipoprotein E (APOE) and A1 (APOA1). A mouse model overexpressing human LDLR was used to test the effect of high levels of liver LDLR on the concentration of HDL cholesterol and APOE-containing HDL subfractions. Pcsk9 knockout males lacking LDLR and APOE were used to test whether LDLR and APOE are necessary for PCSK9-mediated HDL cholesterol regulation. We also investigated the effects of Pcsk9 inactivation on cholesterol efflux capacity of serum using THP-1 and J774.A1 macrophage foam cells and atherosclerotic fatty streak volume in the aortic sinus of Pcsk9 knockout males fed an atherogenic diet.ResultsAPOE and APOA1 were reduced in the same HDL subfractions of Pcsk9 knockout and human LDLR transgenic male mice. In Pcsk9/Ldlr double-knockout mice, HDL cholesterol concentration was lower than in Ldlr knockout mice and higher than in wild-type controls. In Pcsk9/Apoe double-knockout mice, HDL cholesterol concentration was similar to that of Apoe knockout males. In Pcsk9 knockout males, THP-1 macrophage cholesterol efflux capacity of serum was reduced and the fatty streak lesion volume was similar to wild-type controls.ConclusionsIn mice, LDLR and APOE are important factors for PCSK9-mediated HDL regulation. Our data suggest that, although LDLR plays a major role in PCSK9-mediated regulation of HDL cholesterol concentration, it is not the only mechanism and that, regardless of mechanism, APOE is essential. Pcsk9 inactivation decreases the HDL cholesterol concentration and cholesterol efflux capacity in serum, but does not increase atherosclerotic fatty streak volume.

Pharmacologic Profile of the Adnectin BMS-962476, a Small Protein Biologic Alternative to PCSK9 Antibodies for Low-Density Lipoprotein Lowering

“…The decrease in HDL cholesterol levels observed in overexpressing transgenic mice after treatment with BMS-962476 is consistent with other reports showing reductions in HDL with PCSK9 suppression in mouse models (Graham et al, 2008;Choi et al, 2013). It is well established that apoE is a ligand for the LDLR protein family and that some subclasses of HDL particles contain apoE (Gordon et al, 1983), providing a likely mechanism for HDL cholesterol lowering through PCSK9 inhibition.…”

Activation of Adiponectin Receptor Regulates Proprotein Convertase Subtilisin/Kexin Type 9 Expression and Inhibits Lesions in ApoE-Deficient Mice

“…Although whether apoE is able to activate PCSK9 expression has not been reported, deficiency of PCSK9 expression decreases apoE-containing HDL subfractions and reduces cholesterol efflux capacity of the serum. 35 In our study, we determined that long-term ADP355 treatment substantially increased serum apoE levels in wild type mice ( Figure IA in the online-only Data Supplement). These findings imply that the interactions between PCSK9 and apoE need further investigation to elucidate.…”

Variable effects of gender and Western diet on lipid and glucose homeostasis in aged PCSK9‐deficient C57BL/6 mice 性别与西方饮食对CSK9基因缺陷的PC57BL/6老龄小鼠的脂质以及葡萄糖内稳态的不同影响

“…The possible implication of extrahepatic LDLR in the reduction of this lipoprotein in plasma cannot be discounted. The fall of plasma HDL‐C in KO mice may be partially caused by LDLR‐mediated clearance of apolipoprotein E (ApoE)‐containing HDL sub‐fractions …”