title: Lipoprotein(a) catabolism is regulated by proprotein convertase subtilisin/kexin type 9 through the low density lipoprotein receptor.
abstract: Elevated levels of lipoprotein(a) (Lp(a)) have been identified as an independent risk factor for coronary heart disease. Plasma Lp(a) levels are reduced by monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9). However, the mechanism of Lp(a) catabolism in vivo and the role of PCSK9 in this process are unknown. We report that Lp(a) internalization by hepatic HepG2 cells and primary human fibroblasts was effectively reduced by PCSK9. Overexpression of the low density lipoprotein (LDL) receptor (LDLR) in HepG2 cells dramatically increased the internalization of Lp(a). Internalization of Lp(a) was markedly reduced following treatment of HepG2 cells with a function-blocking monoclonal antibody against the LDLR or the use of primary human fibroblasts from an individual with familial hypercholesterolemia; in both cases, Lp(a) internalization was not affected by PCSK9. Optimal Lp(a) internalization in both hepatic and primary human fibroblasts was dependent on the LDL rather than the apolipoprotein(a) component of Lp(a). Lp(a) internalization was also dependent on clathrin-coated pits, and Lp(a) was targeted for lysosomal and not proteasomal degradation. Our data provide strong evidence that the LDLR plays a role in Lp(a) catabolism and that this process can be modulated by PCSK9. These results provide a direct mechanism underlying the therapeutic potential of PCSK9 in effectively lowering Lp(a) levels.
authors.affiliation: From the Department of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario N9B 3P4, Canada.
authors.forename: Rocco
authors.initials: R
authors.lastname: Romagnuolo
authors.affiliation: From the Department of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario N9B 3P4, Canada.
authors.forename: Corey A
authors.initials: CA
authors.lastname: Scipione
authors.affiliation: From the Department of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario N9B 3P4, Canada.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Boffa
authors.affiliation: the Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle, Washington 98109, and.
authors.forename: Santica M
authors.initials: SM
authors.lastname: Marcovina
authors.affiliation: the Laboratory of Biochemical Neuroendocrinology, Institut de Recherches Cliniques de Montréal, Montréal, Québec H2W 1R7, Canada.
authors.forename: Nabil G
authors.initials: NG
authors.lastname: Seidah
authors.affiliation: From the Department of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario N9B 3P4, Canada, mlk@uwindsor.ca.
authors.forename: Marlys L
authors.initials: ML
authors.lastname: Koschinsky
mesh_terms: D001054:Apolipoproteins A / Q000378:metabolism; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D017270:Lipoprotein(a) / Q000097:blood / Q000378:metabolism*; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000378:metabolism*; D021381:Protein Transport; D011973:Receptors, LDL / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism*
chemical_list: D001054:Apolipoproteins A; D017270:Lipoprotein(a); D011973:Receptors, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
keywords: Apolipoprotein(a); Cardiovascular Disease; Hepatocyte; Lipoprotein Receptor; Lipoprotein(a); Metabolism; Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9)