Lipoprotein(a) (Lp[a]) is the most common genetically inherited risk factor for cardiovascular disease. Many aspects of Lp(a) metabolism remain unknown. We assessed the uptake of fluorescent Lp(a) in primary human lymphocytes as well as Lp(a) hepatic capture in a mouse model in which endogenous hepatocytes have been ablated and replaced with human ones. Modulation of LDLR expression with the PCSK9 inhibitor alirocumab did not alter the cellular or the hepatic uptake of Lp(a), demonstrating that the LDL receptor is not a major route for Lp(a) plasma clearance. These results have clinical implications because they underpin why statins are not efficient at reducing Lp(a).
Keywords: 3D, 3-dimensional; AU, arbitrary unit; BSA, bovine serum albumin; ELISA, enzyme-linked immunosorbent assay; FCR, fractional catabolic rate; FRG, Fah(−/−)Rag2(−/−)Il2rg(−/−); HoFH, homozygous familial hypercholesterolemia; LC-MS/MS, liquid chromatography tandem mass spectrometry; LDL, low-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; LDLR, low-density lipoprotein receptor; Lp(a), lipoprotein(a); MFI, mean fluorescence intensity; PBMC, peripheral blood mononuclear cell; PBS, phosphate-buffered saline; PCSK9, proprotein convertase subtilisin/kexin type 9; apoB100, apolipoprotein B100; bodipy, boron dipyrromethene; lipoprotein(a); liver-humanized mice; low-density lipoprotein receptor; proprotein convertase subtilisin/kexin type 9; rPCSK9, recombinant proprotein convertase subtilisin/kexin type 9.
© 2020 The Authors.