PCSK9 Antibodies Treatment Specifically Enhances the Macrophage-specific Reverse Cholesterol Transport Pathway in Heterozygous Familial Hypercholesterolemia

• Published in: JACC. Basic to translational science 2024-10, Vol.9 (10), p.1195-1210
• Main Authors: Borràs, Carla, Canyelles, Marina, Girona, Josefa, Ibarretxe, Daiana, Santos, David, Revilla, Giovanna, Llorente-Cortes, Vicenta, Rotllan, Noemí, Kovanen, Petri T., Jauhiainen, Matti, Lee-Rueckert, Miriam, Masana, Luis, Arrieta, Francisco, Martínez-Botas, Javier, Gómez-Coronado, Diego, Ribalta, Josep, Tondo, Mireia, Blanco-Vaca, Francisco, Escolà-Gil, Joan Carles
• Format: Article
• Language: English
• Subjects: cholesterol; familial hypercholesterolemia; HDL; LDL; macrophages; mice; Original Research - Preclinical; PCSK9; reverse cholesterol transport
• ISSN: 2452-302X; 2452-302X
• DOI: 10.1016/j.jacbts.2024.06.008

[Display omitted] •PCSK9 inhibitors alter the distribution of macrophage-derived cholesterol within lipoproteins in plasma from heterozygous FH subjects during ex vivo cholesterol efflux, reducing LDL's capacity as a cholesterol acceptor while enhancing HDL's acceptor function.•PCSK9 inhibition enhances the macrophage-specific reverse cholesterol transport pathway in human apoB100 transgenic mice, specifically under conditions of heterozygous LDL receptor deficiency.•Anti-PCSK9 therapy facilitates the transfer of LDL-derived cholesterol to feces in heterozygous LDLR-deficient mice expressing human APOB100. We investigated the potential of proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies to restore macrophage cholesterol efflux in subjects with heterozygous familial hypercholesterolemia (FH) and to enhance the macrophage-specific reverse cholesterol transport pathway in mice. Analyses of macrophage-derived cholesterol distribution of plasma from FH patients revealed that low-density lipoprotein (LDL) particles contained less, and high-density lipoprotein particles contained more radiolabeled cholesterol after treatment with either PCSK9 inhibitor. PCSK9 antibodies facilitated the transfer of macrophage-derived cholesterol and LDL-derived cholesterol to feces exclusively in heterozygous LDL receptor-deficient mice expressing human APOB100. PCSK9 inhibitors act as positive regulators of the macrophage-specific reverse cholesterol transport pathway in individuals with heterozygous FH.