Introduction:Statins increase LDL-receptor (LDLR) expression and thus reduce LDL. Statins do not lower lipoprotein (a) (Lp(a)) plasma levels, a liver derived highly atherogenic lipoprotein species. In contrast, PCSK9 inhibitors (e.g. alirocumab) which also increase LDLR cell surface expression, reduce Lp(a). Whether the LDLR plays a role in mediating Lp(a) plasma clearance remains a matter of considerable debate.Hypothesis:The LDLR is not a major contributor to Lp(a) catabolism.Methods:Primary lymphocytes were isolated from normal volunteers, patients with no LDLR (homozygote FH), and patients with isolated elevated Lp(a) (hyper Lp(a)). Cells were incubated sequentially with mevastatin ? PCSK9 ? alirocumab. Fluorescent LDL and Lp(a) cellular uptake were assessed by flow cytometry and expressed in mean fluorescence intensity (MFI). Since none of the common animal models presents the Lp(a) trait, we used the FRG mouse in which mouse hepatocytes have been ablated and repopulated with human hepatocytes. These mice were treated with alirocumab or placebo. Plasma lipids were measured and fluorescent LDL and Lp(a) hepatic capture was assessed 30 minutes post fluorescent lipoproteins injections using 3D Trans-illumination Fluorescence Tomography (arbitrary units).Results:LDL cellular uptake followed the pattern of LDLR cell surface expression in human primary lymphocytes (i.e. increased by statins and reduced by PCSK9 treatment or in FH cells vs. controls). In contrast, Lp(a) cellular uptake was similar in lymphocytes isolated from controls [MFI 210?18], FH [MFI 218?25], or hyper Lp(a) patients [?MFI 207?28] and was insensitive to statin, PCSK9 or alirocumab treatments. In FRG mice, alirocumab reduced LDL-cholesterol (-51%, p=0.008) and Lp(a) levels (-48%, p=0.031). As anticipated, vs. placebo alirocumab reduced fluorescent LDL hepatic capture (1.06?0.11 vs. 0.56?0.12 AU, p=0.017) but not fluorescent Lp(a) capture (2.18?0.43 vs. 2.05?0.49 AU, p=0.85) in FRG mice.Conclusion:The LDLR does not play a major physiological role in plasma Lp(a) clearance since modulating LDLR expression genetically or pharmacologically does not significantly modulate Lp(a) cellular uptake ex vivo nor Lp(a) plasma hepatic capture in vivo.