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.
Highlights
IntroductionWe investigated the molecular mechanism by which PCSK9 regulates HDL cholesterol concentration and whether Pcsk inactivation might affect cholesterol efflux capacity of serum and atherosclerotic fatty streak volume
Studies in animals showed that PCSK9 is involved in HDL metabolism
apolipoprotein E (APOE)-containing HDL subfractions are decreased in Pcsk9 KO mice We investigated whether APOE reduction in the non-HDL depleted serum (NHDS) of Pcsk9 KO was due to reduced APOE-containing HDL subfractions
Summary
We investigated the molecular mechanism by which PCSK9 regulates HDL cholesterol concentration and whether Pcsk inactivation might affect cholesterol efflux capacity of serum and atherosclerotic fatty streak volume. The major molecular function neutralizing antibodies against PCSK9 reduced HDL cholesterol concentrations for the first seven days of treatment [8]. The molecular mechanism by which PCSK9 regulates HDL cholesterol concentration has not been investigated. PCSK9-mediated regulation of APOE levels in HDL may be a key mechanism that determines HDL cholesterol concentration. We show that increased LDLR decreases APOE-containing HDL subfractions and HDL cholesterol concentrations in mice. We show that, Pcsk KO reduces HDL cholesterol concentration and cholesterol efflux capacity in serum, there is no significant impact on early atherogenesis
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