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Background  Studies 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.    Methods  Mass 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.    Results  APOE 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.    Conclusions  In 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.

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