Genetics
Genome-scale CRISPR screen resolves a long-standing controversy: the LDL receptor, not a dedicated protein, is the main gateway for Lp(a) uptake (bioRxiv 2024)
Original title: Functional interrogation of cellular Lp(a) uptake by genome-scale CRISPR screening
The identity of the receptor or receptors that clear Lp(a) from circulation has been controversial. This study performed a genome-scale CRISPR screen in HuH7 liver cells to functionally test all potential regulators of cellular Lp(a) uptake. The strongest positive and negative hits were LDLR (the LDL receptor) and MYLIP (encoding its ubiquitin ligase IDOL), respectively, with other genes known to regulate LDLR also showing significant effects; no other candidate gene, including previously proposed dedicated Lp(a) receptors, had a significant effect on uptake. The authors validated that LDLR expression functionally influences HuH7 Lp(a) uptake, confirmed direct in vitro binding between the LDLR extracellular domain and purified Lp(a), and found that loss-of-function LDLR variants were associated with higher circulating Lp(a) in the UK Biobank cohort. These convergent functional and human genetic findings support the LDL receptor, rather than a dedicated Lp(a)-specific receptor, as the central mediator of hepatic Lp(a) clearance.
Original abstract
An elevated level of lipoprotein(a), or Lp(a), in the bloodstream has been causally linked to the development of atherosclerotic cardiovascular disease and calcific aortic valve stenosis. Steady state levels of circulating lipoproteins are modulated by their rate of clearance, but the identity of the Lp(a) uptake receptor(s) has been controversial. In this study, we performed a genome-scale CRISPR screen to functionally interrogate all potential Lp(a) uptake regulators in HuH7 cells. Strikingly, the top positive and negative regulators of Lp(a) uptake in our screen were LDLR and MYLIP, encoding the LDL receptor and its ubiquitin ligase IDOL, respectively. We also found a significant correlation for other genes with established roles in LDLR regulation. No other gene products, including those previously proposed as Lp(a) receptors, exhibited a significant effect on Lp(a) uptake in our screen. We validated the functional influence of LDLR expression on HuH7 Lp(a) uptake, confirmed in vitro binding between the LDLR extracellular domain and purified Lp(a), and detected an association between loss-of-function LDLR variants and increased circulating Lp(a) levels in the UK Biobank cohort. Together, our findings support a central role for the LDL receptor in mediating Lp(a) uptake by hepatocytes.
Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.