Inhibitory effect of PCSK9 on Abca1 protein expression and cholesterol efflux in macrophages. (January 2017)

• Record Type: Journal Article
• Authors: Adorni, Maria Pia; Cipollari, Eleonora; Favari, Elda; Zanotti, Ilaria; Zimetti, Francesca; Corsini, Alberto; Ricci, Chiara; Bernini, Franco; Ferri, Nicola
• Is Part Of: Atherosclerosis. Volume 256(2017)
• Page Start: 1
• Page End: 6
• Publication Date: 2017-01
• Subjects: PCSK9 -- Cholesterol efflux -- ABCA1 -- Macrophage; Arteriosclerosis -- Periodicals; Electronic journals; 616.136
• DOI: 10.1016/j.atherosclerosis.2016.11.019
• Languages: English
• ISSNs: 0021-9150

Abstract

Abstract: Background and aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) may have extra-hepatic effects on cholesterol homeostasis of vascular macrophages. In this study, we aimed to investigate PCSK9 role on the anti-atherogenic process of ATP binding cassette transporter A1 (Abca1)-mediated cholesterol efflux. Methods: Abca1-mediated cholesterol efflux was evaluated by a radioisotopic technique in mouse peritoneal macrophages (MPM) from wild-type (WT) or LDL receptor knock-out ( Ldlr −/− ) mice exposed to human recombinant PCSK9, in the presence of liver X receptor/retinoid X receptor (LXR/RXR) ligands or acetylated LDL (AcLDL) to stimulate Abca1 expression. Protein and gene expression was evaluated by Western blot and quantitative real time PCR, respectively. Results: PCSK9 inhibited Abca1-mediated cholesterol efflux induced by LXR/RXR agonists in WT MPM (−55%, p < 0.05) but not in Ldlr −/− MPM. This effect was fully abrogated by the co-incubation with an anti -PCSK9 antibody. The inhibition of Abca1-dependent efflux induced by PCSK9 was associated with a reduction of Abca1 protein expression only in WT cells. Abca1 gene expression was significantly downregulated by PCSK9 in WT macrophages (−64%, p < 0.001) and, to a lesser extent, in MPM lacking Ldlr (−35%, p < 0.001). The inhibitory effect on Abca1-mediated efflux was also confirmed in AcLDL-treated macrophages. PCSK9 had a marginal or no effect on the expression of the lipid transporters Sr-b1 and Abcg1 . Conclusions: PCSK9 plays a direct role on Abca1-mediated cholesterol efflux through a downregulation of Abca1 gene and Abca1 protein expression. This extrahepatic effect may influence relevant steps in the pathogenesis of atherosclerosis, such as foam cell formation. Highlights: PCSK9 specifically inhibits Abca1-mediated cholesterol efflux in WT, but not in Ldlr −/− macrophages. PCSK9 inhibits Abca1 protein expression in WT, but not in Ldlr −/− macrophages. PCSK9, by inhibiting cholesterol efflux process, may facilitate foam cell formation, a hallmark of atherosclerosis.