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

Publisher: Elsevier Country of Publication: United States NLM ID: 0376606 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1539-7262 (Electronic) Linking ISSN: 00222275 NLM ISO Abbreviation: J Lipid Res Subsets: MEDLINE

Publication: 2021- : [New York] : Elsevier
Original Publication: Memphis, Lipid Research, inc.

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

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.
(Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.)

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

0 (Antibodies)
0 (Apolipoproteins E)
0 (Cholesterol Ester Transfer Proteins)
0 (Receptors, LDL)
97C5T2UQ7J (Cholesterol)
EC 3.4.21.- (PCSK9 protein, human)
EC 3.4.21.- (Proprotein Convertase 9)
EC 3.4.21.- (Proprotein Convertases)
EC 3.4.21.- (Serine Endopeptidases)

Date Created: 20140927 Date Completed: 20151015 Latest Revision: 20220408

20221213

PMC4617138

10.1194/jlr.M053207

25258384