Genetics
A genome-scale CRISPR screen identifies the LDL receptor, not a disputed alternative, as the key hepatocyte gateway for Lp(a) uptake (Atherosclerosis 2025)
Original title: Functional interrogation of cellular Lp(a) uptake by genome-scale CRISPR screening
This study performed a genome-scale CRISPR screen in HuH7 liver cells to resolve the long-disputed identity of the receptor(s) mediating cellular Lp(a) uptake and clearance. The top positive and negative regulators of Lp(a) uptake were LDLR (encoding the LDL receptor) and MYLIP (encoding its ubiquitin ligase IDOL), respectively, alongside other genes with established roles in LDLR regulation; no other candidate genes, including previously proposed alternative Lp(a) receptors, showed a significant effect in the screen. The authors validated LDLR's functional role in HuH7 Lp(a) uptake, confirmed direct binding between the LDL receptor's extracellular domain and purified Lp(a) using biolayer interferometry, and found loss-of-function LDLR variants associated with higher circulating Lp(a) in the UK Biobank cohort. The findings support a central role for the LDL receptor, not the various alternative candidates proposed over the years, in mediating hepatocyte Lp(a) clearance.
Original abstract
Background And Aims: 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.
Methods: We performed a genome-scale CRISPR screen to functionally interrogate all potential Lp(a) uptake regulators in HuH7 cells. Screen validation was performed by single gene disruption and overexpression. Direct binding between purified lipoproteins and recombinant protein was tested using biolayer interferometry. An association between human genetic variants and circulating Lp(a) levels was analyzed in the UK Biobank cohort.
Results: 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.
Conclusions: 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.