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

Lipids in Health and Disease

Ron Korstanje³  Annik Prat¹  Bin Deng⁴  Blake R Peterson⁵  Ujala Srivastava²  Aleksandra Aljakna²  Seungbum Choi³ 

[1]Laboratory of Biochemical Neuroendocrinology, Institut de Recherches Cliniques de Montréal, affiliated to the University of Montreal, Montreal, QC Canada

[2]The Jackson Laboratory, Bar Harbor, ME USA

[3]Graduate School of Biomedical Sciences, University of Maine, Orono, ME USA

[4]Department of Biology/VGN Proteomics Facility, University of Vermont, Burlington, VT USA

[5]Department of Medicinal Chemistry, University of Kansas, Lawrence, KS USA

关键词: Proprotein convertase subtilisin/kexin type 9;    Macrophage foam cell;    Low-density lipoprotein receptor;    Atherosclerotic fatty streak;    Apolipoprotein E;   

Others  :  834240
DOI  :  10.1186/1476-511X-12-112

 received in 2013-05-29, accepted in 2013-07-22,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Choi et al.; licensee BioMed Central Ltd.

【 图 表 】

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