Publication in detail

J Lipid Res. 2014 Sep 25. pii: jlr.M053207. [Epub ahead of print]

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

Ason, B; van der Hoorn, JW; Chan, J; Lee, E; Pieterman, EJ; Nguyen, KK; Di, M; Shetterly, S; Tang, J; Yeh, WC; Schwarz, M; Jukema, JW; Scott, R; Wasserman, SM; Princen, HM; Jackson, S

Amgen, Inc, Thousand Oaks, CA, United States; TNO - Metabolic Health Research, Netherlands; Leiden University Medical Center, Netherlands.

Abstract:
Low density lipoprotein 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 apolipoprotein E (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 triglycerides (-36%) in APOE*3Leiden.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.

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