PCSK9 inhibition fails to alter hepatic LDLR, circulating cholesterol, and atherosclerosis in the absence of ApoE

J Lipid Res. 2014 Nov;55(11):2370-9. doi: 10.1194/jlr.M053207. Epub 2014 Sep 25.

Abstract

LDL cholesterol (LDL-C) contributes to coronary heart disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases LDL-C by inhibiting LDL-C clearance. The therapeutic potential for PCSK9 inhibitors is highlighted by the fact that PCSK9 loss-of-function carriers exhibit 15-30% lower circulating LDL-C and a disproportionately lower risk (47-88%) of experiencing a cardiovascular event. Here, we utilized pcsk9(-/-) mice and an anti-PCSK9 antibody to study the role of the LDL receptor (LDLR) and ApoE in PCSK9-mediated regulation of plasma cholesterol and atherosclerotic lesion development. We found that circulating cholesterol and atherosclerotic lesions were minimally modified in pcsk9(-/-) mice on either an LDLR- or ApoE-deficient background. Acute administration of an anti-PCSK9 antibody did not reduce circulating cholesterol in an ApoE-deficient background, but did reduce circulating cholesterol (-45%) and TGs (-36%) in APOE*3Leiden.cholesteryl ester transfer protein (CETP) mice, which contain mouse ApoE, human mutant APOE3*Leiden, and a functional LDLR. Chronic anti-PCSK9 antibody treatment in APOE*3Leiden.CETP mice resulted in a significant reduction in atherosclerotic lesion area (-91%) and reduced lesion complexity. Taken together, these results indicate that both LDLR and ApoE are required for PCSK9 inhibitor-mediated reductions in atherosclerosis, as both are needed to increase hepatic LDLR expression.

Keywords: anti-proprotein convertase subtilisin/kexin type 9 antibody; apolipoprotein E; low density lipoprotein receptor; proprotein convertase subtilisin/kexin type 9.

MeSH terms

  • Animals
  • Antibodies / immunology
  • Apolipoproteins E / deficiency*
  • Atherosclerosis / blood
  • Atherosclerosis / enzymology
  • Atherosclerosis / genetics
  • Atherosclerosis / metabolism*
  • Cholesterol / blood*
  • Cholesterol Ester Transfer Proteins / metabolism
  • Female
  • Gene Knockout Techniques
  • Humans
  • Liver / drug effects
  • Liver / metabolism*
  • Mice
  • Proprotein Convertase 9
  • Proprotein Convertases / deficiency
  • Proprotein Convertases / genetics
  • Proprotein Convertases / immunology
  • Proprotein Convertases / metabolism*
  • Receptors, LDL / metabolism*
  • Serine Endopeptidases / deficiency
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / immunology
  • Serine Endopeptidases / metabolism*

Substances

  • Antibodies
  • Apolipoproteins E
  • Cholesterol Ester Transfer Proteins
  • Receptors, LDL
  • Cholesterol
  • PCSK9 protein, human
  • Proprotein Convertase 9
  • Proprotein Convertases
  • Serine Endopeptidases