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Cited by 6Lipoproteins and Cardiovascular HealthCholesterol and Lipid MetabolismLipid metabolism and disorders

The DOI matches its Crossref record; 93 of the 93 references it cites were found in a registry or an index; 6 of the 70 sources its claims cite were checked for support.

Functional interrogation of cellular Lp(a) uptake by genome-scale CRISPR screening

Open access
Khan, Taslima G., Bragazzi Cunha, Juliana, Raut, Chinmay, Burroughs, Michael, Vyas, Hitarthi S., Leix, Kyle, Goonewardena, Sascha N., Smrcka, Alan V., Speliotes, Elizabeth K., Emmer, Brian T.·2025·Atherosclerosis
DOI 10.1016/j.atherosclerosis.2025.119174PMC PMC12011201

Published version of a preprint

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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.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

A genome-scale CRISPR knockout screen in HuH7 cells identifies LDLR as the top positive regulator and MYLIP/IDOL as the top negative regulator of cellular Lp(a) uptake, with no other proposed Lp(a) receptor showing a significant effect. Validation, direct binding, and UK Biobank analyses support a central role for the LDL receptor in hepatocyte Lp(a) uptake.

Key findings

  • In the CRISPR screen, disruption of *LDLR* caused the most significant decrease in Lp(a) uptake and disruption of *MYLIP* caused the most significant increase; at FDR < 5%, no other genes were significant, while at FDR < 20%, 8 additional genes were identified, including *SCAP* and *MBTPS2*.
  • LDLR perturbation functionally modulated HuH7 Lp(a) uptake: LDLR disruption abrogated uptake and was rescued by LDLR cDNA, while LDLR overexpression augmented uptake; LDLR-disrupted cells showed ~61% reduction in Lp(a) uptake versus ~87% reduction for LDL uptake.
  • Biolayer interferometry showed concentration-dependent, LDLR-dependent binding of Lp(a) to the LDLR extracellular domain, though binding was lesser than LDL and nonsaturating; HDL showed no LDLR binding.
  • In 359,090 UK Biobank individuals, 225 heterozygous carriers of 25 pathogenic LDLR alleles had 9.2% higher Lp(a) levels (p = 6.9 × 10⁻³) and 32.3% higher LDL cholesterol levels (p = 4.1 × 10⁻¹¹⁶) than noncarriers.

Methods

  • Genome-scale CRISPR knockout screen using the GeCKOv2 library in HuH7 cells, with 3 independent replicates, ~60 million cells per replicate, MOI ~0.5, 14 days of editing, incubation with 20 μg/mL pHrodo iFL Red-labeled Lp(a), sorting of 10% least and greatest uptake populations, and MAGeCK analysis.
  • Validation by single-gene disruption and overexpression, flow cytometry, apo(a) ELISA, immunofluorescence, and biolayer interferometry using recombinant LDLR extracellular domain and purified lipoproteins.
  • UK Biobank whole-exome sequencing analysis of 359,090 individuals with serum Lp(a), including burden testing of a pre-defined set of 61 ClinVar pathogenic LDLR variants and adjustment for age, sex, ancestry, and lipid-lowering medications.

Limitations

  • Stated in the paper: CRISPR knockout screens may miss essential genes, genes poorly expressed in HuH7 cells, inefficiently edited targets, cell-autonomous-only mechanisms (e.g., PCSK9), small effect sizes, and functionally redundant genes; lack of significance is not definitive evidence against a role in Lp(a) uptake.
  • Stated in the paper: biolayer interferometry could not yield an exact binding affinity for Lp(a)-LDLR due to moderate/weak affinity and concentrations below the Kd, and the study cannot conclude whether direct binding is sufficient for physiologically relevant in vivo binding; LDL may outcompete Lp(a) when receptors are limited.
  • Stated in the paper: UK Biobank analysis could not directly assess LPA KIV2 copy number variants, and statin usage may confound or mask Lp(a) associations; evident from the text, the findings rely on a commercial single-donor Lp(a) preparation and the HuH7 hepatoma cell model, which may not fully reflect in vivo hepatocyte biology.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.atherosclerosis.2025.119174

Cites

93 of 93 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

6 of 70 cited sources checked · 3 supported · 0 flagged · accuracy not yet measured

  • Study design and conductcitation

    Individual cells with disrupted PCSK9 will remain sensitive to the extracellular PCSK9 secreted by neighboring cells, precluding their development of a LDLR-mediated phenotype in this study and in prior pooled CRISPR screens.

    “For example, individual cells with disrupted PCSK9 will remain sensitive to the extracellular PCSK9 secreted by neighboring cells, precluding their development of a LDLR-mediated phenotype in this study and in prior pooled CRISPR screens for LDL uptake or LDLR abundance56,80,93.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [56] Emmer, 2021, Genome-scale CRISPR screening for modifiers of cellular LDL uptake, PLoS Genet. source

      The Discussion (page not provided) says that PCSK9-targeted cells remain susceptible to PCSK9 secreted by neighboring cells, preventing changes in LDLR abundance and LDL uptake in this screen. It does not establish that the same outcome occurred in the prior pooled CRISPR screens mentioned in the citing sentence. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [80] Smith, 2022, Cold shock domain-containing protein E1 is a posttranscriptional regulator of the LDL receptor, Sci. Transl. Med. source

      The Results sections describe a pooled CRISPRi screen for surface LDLR abundance and state that PCSK9 acts extracellularly in LDLR regulation. They do not say that PCSK9-disrupted cells remained sensitive to PCSK9 from neighboring cells, or that this prevented an LDLR phenotype in this or prior pooled screens. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
    • cites [93] Hamilton, 2023, Systematic elucidation of genetic mechanisms underlying cholesterol uptake, Cell Genom source
  • Premisecitation

    A prior genome-scale CRISPR screen successfully identified regulators of cellular LDL endocytosis.

    “We previously applied a genome-scale CRISPR screen to successfully identify regulators of cellular LDL endocytosis56.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [56] Emmer, 2021, Genome-scale CRISPR screening for modifiers of cellular LDL uptake, PLoS Genet. source
  • Findingown data

    The 8 additional genes identified at FDR < 20% included the canonical LDLR regulators SCAP and MBTPS2.

    “This group included the canonical LDLR regulators SCAP and MBTPS2”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: HuH7 cells are a valid model of hepatocytes for Lp(a) uptake.
    • Rests on an assumption: No prior study has systematically and unbiasedly interrogated all potential Lp(a) receptors in the same experimental context.
  • Findingown data

    At an FDR < 5%, no genes other than LDLR and MYLIP had a significant role in Lp(a) uptake in the screen.

    “Using a stringent cutoff for screen analysis (false discovery rate, or FDR < 5%), we identified no other genes with a significant role in Lp(a) uptake.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: HuH7 cells are a valid model of hepatocytes for Lp(a) uptake.
    • Rests on an assumption: No prior study has systematically and unbiasedly interrogated all potential Lp(a) receptors in the same experimental context.
  • Findingown data

    Overexpression of LDLR on a wild-type background significantly augmented cellular uptake of Lp(a) in HuH7 cells.

    “we also found that overexpression of LDLR on a wild-type background significantly augmented cellular uptake of Lp(a)”
    Quote in the paperSubstantial claim
    • Rests on an assumption: HuH7 cells are a valid model of hepatocytes for Lp(a) uptake.
  • It may state two separate claims as one. 9
  • Probably not a substantial claim. 26
  • The quote only partly states this claim. 1

  • It may state two separate claims as one.

    Interpretationown data

    The smaller genetic effect on Lp(a) is consistent with our lipoprotein uptake studies and in vitro binding studies.

    “This finding is consistent with our lipoprotein uptake studies that revealed a less pronounced defect in LDLR-disrupted cells for Lp(a) uptake (~61% reduction) compared to LDL uptake (~87% reduction56), and with our in vitro binding studies showing a reduced affinity for LDLR binding to Lp(a) relative to LDL.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [56] Emmer, 2021, Genome-scale CRISPR screening for modifiers of cellular LDL uptake, PLoS Genet. source

  • It may state two separate claims as one.

    Premisecitation

    The prior CRISPR screen detected novel regulators of LDL uptake that were reproducible across independent replicates and during follow-up testing.

    “We also detected novel regulators of LDL uptake that were reproducible across independent replicates and during follow up testing56,57.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [56] Emmer, 2021, Genome-scale CRISPR screening for modifiers of cellular LDL uptake, PLoS Genet. source
    • cites [57] Khan, 2022, The small GTPase RAB10 regulates endosomal recycling of the LDL receptor and transferrin receptor in hepatocytes, J. Lipid Res. source

      The Abstract and Discussion report that a prior CRISPR screen identified RAB10 and other modifiers of LDL uptake. The Results section, “RAB10 regulates the cellular uptake of LDL and transferrin,” reports follow-up experiments confirming RAB10’s effect, with independent biological replicates shown in Fig. 1. Our copy does not establish that the screen’s novel regulators generally were reproducible across independent screen replicates and follow-up tests. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Findingown data

    The magnitude of the effect of LDLR genotypes on Lp(a) levels was notably smaller than that observed for LDL levels, with Lp(a) increased by ~9% and LDL by ~32% among pathogenic LDLR allele carriers.

    “While we did find a significant association between LDLR genotypes and Lp(a) levels, the magnitude of this effect was notably smaller than that observed for LDL levels, with the former increased by ~9% and the latter ~32% among pathogenic LDLR allele carriers.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    LDL showed concentration-dependent binding to LDLR-immobilized sensors but not to control sensors, while HDL showed no evidence of LDLR binding.

    “we observed a concentration-dependent shift in refracted light for LDL with LDLR-immobilized sensors but not with control streptavidin-coated sensors alone, while parallel reactions with HDL revealed no evidence of LDLR binding”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    The association between pathogenic LDLR alleles and higher Lp(a) levels was statistically significant and of comparable effect size across raw or adjusted Lp(a) levels, untransformed or rank-based inverse-normalized values, all ancestries or Europeans only, and with or without adjustment for rs10455872.

    “This relative increase in Lp(a) levels was statistically significant and of a comparable effect size whether analyzing raw or adjusted Lp(a) levels, untransformed or rank-based inverse-normalized values, all ancestries in the cohort or Europeans only, or with or without adjustment for genotype at the rs10455872 SNP”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Other studies of individuals with Familial Hypercholesterolemia have not reported an increase in Lp(a) levels.

    “Some studies of individuals with Familial Hypercholesterolemia (FH) have reported an increase in Lp(a) levels40-42, but others have not43-45 and suggested that the former may have been confounded by diagnostic ascertainment bias and/or unequal distributions of LPA risk alleles between FH and non-FH populations44,45.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [43] Carmena, 1996, Lp(a) levels and atherosclerotic vascular disease in a sample of patients with familial hypercholesterolemia sharing the same gene defect, Arterioscler. Thromb. Vasc. Biol. source
    • cites [44] Trinder, 2020, Ascertainment bias in the association between elevated lipoprotein(a) and familial hypercholesterolemia, J. Am. Coll. Cardiol. source
    • cites [45] Langsted, 2016, High lipoprotein(a) as a possible cause of clinical familial hypercholesterolaemia: a prospective cohort study, Lancet Diabetes Endocrinol. source

  • Probably not a substantial claim.

    Study design and conductown data

    The UK Biobank analysis controlled for age, age2, sex, and the first 10 genetic principal components.

    “Analysis was performed controlling for age (Datafield 21003), age2, sex (Datafield 22001), and the first 10 genetic principal components (Datafield 22009).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductreasoning

    Loss-of-function CRISPR screens have limited ability to detect functionally redundant genes.

    “Finally, loss-of-function CRISPR screens have limited ability to detect functionally redundant genes.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Study design and conductreasoning

    The expression of any single gene may vary from its in vivo state in hepatocytes, potentially leading to a false negative result if a putative Lp(a) receptor is poorly expressed.

    “Second, although HuH7 cells have been shown to serve as excellent models for lipoprotein uptake by hepatocytes92, the expression of any single gene may vary from its in vivo state in hepatocytes, potentially leading to a false negative result if a putative Lp(a) receptor is poorly expressed.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    A recent GWAS of 371,212 individuals in the UK Biobank did find an association between Lp(a) levels and common variants at the LDLR locus.

    “Multiple genome-wide association studies (GWAS) did not find an association between Lp(a) levels and common variants at the LDLR locus10,46,47, but a recent GWAS of 371,212 individuals in the UK Biobank did48.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Said, 2021, Genome-wide association study and identification of a protective missense variant on lipoprotein(a) concentration: protective missense variant on lipoprotein(a) concentration-brief report, Arterioscler. Thromb. Vasc. Biol. source

  • Probably not a substantial claim.

    Premisecitation

    A recent study found that statin treatment caused a significant increase in LPA expression in HepG2 cells.

    “Intriguingly, a recent study also found that statin treatment caused a significant increase in LPA expression in HepG2 cells19.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Tsimikas, 2020, Statin therapy increases lipoprotein(a) levels, Eur. Heart J. source

  • Probably not a substantial claim.

    Study design and conductnone given

    Cells were maintained at a minimum of ~30 million cells, representing >200X library coverage, throughout the screen.

    “Cells were passaged every 2-3 days to maintain logarithmic phase growth with a minimum of ~30 million cells, representing >200X library coverage, at all times.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.

    Interpretationnone given

    The basis for the inconsistent findings on LDLR and Lp(a) remains unclear but may be related to differences in experimental design, including methods of Lp(a) purification and measurement.

    “The basis for these inconsistent findings, both in relation to each other and to our findings, remains unclear but may be related to differences in experimental design, including methods of Lp(a) purification and measurement.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The quote only partly states this claim.

    Study design and conductown data

    We analyzed for potential confounding variables that might drive the association between LDLR genotype and Lp(a) levels.

    “We analyzed for potential confounding variables that might drive this association.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Study design and conductcitation

    The UK Biobank analysis used a pre-defined set of 61 ClinVar variants annotated as pathogenic based on ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel consensus guidelines.

    “Burden testing was performed using a pre-defined set of 61 variants annotated in ClinVar73 (accession SCV004022429.1) as pathogenic based on Clinical Genome Resource (ClinGen) Familial Hypercholesterolemia Variant Curation Expert Panel consensus guidelines74.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [73] Landrum, 2014, ClinVar: public archive of relationships among sequence variation and human phenotype, Nucleic Acids Res. source
    • cites [74] Chora, 2022, The clinical genome Resource (ClinGen) familial hypercholesterolemia variant curation expert panel consensus guidelines for LDLR variant classification, Genet. Med. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Multiple studies in cells have provided support for an interaction between Lp(a) and LDLR.

    “Indeed, multiple studies in cells have provided support for an interaction between Lp(a) and LDLR27-30.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [27] Floren, 1981, Uptake of Lp (a) lipoprotein by cultured fibroblasts, Biochem. Biophys. Res. Commun. source
    • cites [28] Krempler, 1983, Studies on the role of specific cell surface receptors in the removal of lipoprotein (a) in man, J. Clin. Investig. source
    • cites [29] Tam, 1996, Interaction of a recombinant form of apolipoprotein[a] with human fibroblasts and with the human hepatoma cell line HepG2, J. Lipid Res. source
    • cites [30] Romagnuolo, 2015, Lipoprotein(a) catabolism is regulated by proprotein convertase subtilisin/kexin type 9 through the low density lipoprotein receptor, J. Biol. Chem. source

  • Probably not a substantial claim.

    Premisecitation

    Other studies have found no influence of LDLR on cellular Lp(a) binding or uptake in vitro.

    “However, other studies have found no influence of LDLR on cellular Lp(a) binding or uptake in vitro31-34.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [31] Reblin, 1997, Cellular uptake of lipoprotein[a] by mouse embryonic fibroblasts via the LDL receptor and the LDL receptor-related protein, J. Lipid Res. source
    • cites [32] Chemello, 2020, Lipoprotein(a) cellular uptake ex vivo and hepatic capture in vivo is insensitive to PCSK9 inhibition with alirocumab, JACC Basic Transl Sci source
    • cites [33] Sharma, 2017, Recycling of apolipoprotein(a) after PlgRKT-mediated endocytosis of lipoprotein(a), Circ. Res. source
    • cites [34] Villard, 2016, PCSK9 modulates the secretion but not the cellular uptake of lipoprotein(a) ex vivo: an effect blunted by alirocumab, JACC Basic Transl Sci source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Other studies have demonstrated reduced Lp(a) cellular binding relative to LDL for primary human hepatocytes, HepG2, and Hep3B cells.

    “Other studies have also demonstrated reduced Lp(a) cellular binding relative to LDL for primary human hepatocytes, HepG2, and Hep3B cells82,83, with the caveat that each study varied in its particular experimental conditions.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [82] Kostner, 1993, Interaction of Lp(a) and of apo(a) with liver cells, Arterioscler. Thromb. source
    • cites [83] Snyder, 1994, Binding and degradation of lipoprotein(a) and LDL by primary cultures of human hepatocytes. Comparison with cultured human monocyte-macrophages and fibroblasts, Arterioscler. Thromb. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data

    The UK Biobank analysis included a parallel analysis with adjustment for genotype at rs10455872.

    “A parallel analysis was also conducted that included genotype at the rs10455872 SNP as a covariate.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductreasoning

    We cannot conclude whether cooperative interactions with other molecules at the cell surface might have a role in increasing the affinity of Lp(a)-LDLR binding.

    “Although our findings indicate direct binding between Lp(a) and LDLR in vitro, we cannot conclude whether this interaction is sufficient for physiologically relevant binding in vivo or if cooperative interactions with other molecules at the cell surface might have a role in increasing the affinity of Lp(a)-LDLR binding.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Some studies of individuals with Familial Hypercholesterolemia have reported an increase in Lp(a) levels.

    “Some studies of individuals with Familial Hypercholesterolemia (FH) have reported an increase in Lp(a) levels40-42, but others have not43-45 and suggested that the former may have been confounded by diagnostic ascertainment bias and/or unequal distributions of LPA risk alleles between FH and non-FH populations44,45.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [40] Lingenhel, 1998, Concentrations of the atherogenic Lp(a) are elevated in FH, Eur. J. Hum. Genet. source
    • cites [41] Alonso, 2014, Lipoprotein(a) levels in familial hypercholesterolemia: an important predictor of cardiovascular disease independent of the type of LDL receptor mutation, J. Am. Coll. Cardiol. source
    • cites [42] Kraft, 2000, Lipoprotein(a) in homozygous familial hypercholesterolemia, Arterioscler. Thromb. Vasc. Biol. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Several other candidate Lp(a) receptors have been proposed, including other lipoprotein receptors, toll-like receptors, scavenger receptors, lectins, and plasminogen receptors.

    “Over time, several other candidate Lp(a) receptors have been proposed, including other lipoprotein receptors49,50, toll-like receptors51, scavenger receptors52,53, lectins26,54, and plasminogen receptors29,33.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [49] Argraves, 1997, The atherogenic lipoprotein Lp(a) is internalized and degraded in a process mediated by the VLDL receptor, J. Clin. Investig. source
    • cites [50] Marz, 1993, Heterogeneous lipoprotein (a) size isoforms differ by their interaction with the low density lipoprotein receptor and the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor, FEBS Lett. source
    • cites [51] Seimon, 2010, Atherogenic lipids and lipoproteins trigger CD36-TLR2-dependent apoptosis in macrophages undergoing endoplasmic reticulum stress, Cell Metab. source
    • cites [52] Yang, 2013, Scavenger receptor-BI is a receptor for lipoprotein(a), J. Lipid Res. source
    • cites [53] Sharma, 2015, Lipoprotein (a) upregulates ABCA1 in liver cells via scavenger receptor-B1 through its oxidized phospholipids, J. Lipid Res. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    One study in humans found a defect in Lp(a) catabolism for patients with Familial Hypercholesterolemia.

    “Likewise, while one study in humans found a defect in Lp(a) catabolism for patients with Familial Hypercholesterolemia (characterized by a defect in LDLR-mediated LDL uptake)28, other studies did not37-39.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Krempler, 1983, Studies on the role of specific cell surface receptors in the removal of lipoprotein (a) in man, J. Clin. Investig. source

  • It may state two separate claims as one.

    Premisecitation

    Steady state levels of circulating Lp(a) depend on its rate of clearance, which occurs primarily in the liver.

    “The steady state level of circulating Lp(a) also depends on its rate of clearance, which occurs primarily in the liver25,26.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [25] Cain, 2005, Lipoprotein [a] is cleared from the plasma primarily by the liver in a process mediated by apolipoprotein [a], J. Lipid Res. source
    • cites [26] Hrzenjak, 2003, Galactose-specific asialoglycoprotein receptor is involved in lipoprotein (a) catabolism, Biochem. J. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductcitation

    We were unable to calculate an exact binding affinity for the interaction between Lp(a) and LDLR.

    “We were unable to calculate an exact binding affinity for the interaction between Lp(a) and LDLR, a known limitation of BLI for moderate to weak affinity interactions and analyte concentrations below the Kd84.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [84] Jug, 2024, Biolayer interferometry and its applications in drug discovery and development, TrAC, Trends Anal. Chem. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Other studies in humans did not find a defect in Lp(a) catabolism for patients with Familial Hypercholesterolemia.

    “other studies did not37-39.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [37] Rader, 1995, The low density lipoprotein receptor is not required for normal catabolism of Lp(a) in humans, J. Clin. Investig. source
    • cites [38] Knight, 1991, Catabolism of lipoprotein(a) in familial hypercholesterolaemic subjects, Atherosclerosis source
    • cites [39] Knight, 1994, Lp(a) catabolism in hypercholesterolaemic individuals, Chem. Phys. Lipids source

  • Probably not a substantial claim. It may state two separate claims as one.

    Study design and conductown data

    The UK Biobank analysis adjusted lipoprotein levels for lipid-lowering medication use and controlled for age, sex, and ancestry.

    “We adjusted lipoprotein levels for the use of lipid-lowering medications and controlled for age, sex, and ancestry (Supplemental Table 3).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Study design and conductown data

    The CRISPR screen was performed in 3 independent biological replicates.

    “For each of 3 independent biologic replicates, we transduced ~60 million HuH7 cells at multiplicity of infection (MOI) ~0.5”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    We could not directly assess LPA KIV2 copy number variants in the UKBB cohort to assess for a difference between groups.

    “We found the association between LDLR genotype and Lp(a) levels remained significant after accounting for the rs10455872 genotype that tags a narrower range of LPA alleles10, but we could not directly assess LPA KIV2 copy number variants in the UKBB cohort to assess for a difference between groups.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Another study reported that statin usage may decrease rather than increase Lp(a) levels among FH patients.

    “Intriguingly, another study reported that statin usage may decrease rather than increase Lp(a) levels among FH patients85.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [85] van Wissen, 2003, Long term statin treatment reduces lipoprotein(a) concentrations in heterozygous familial hypercholesterolaemia, Heart source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductcitation

    The UK Biobank analysis accounted for genetic relatedness using array genotypes.

    “Genetic relatedness was accounted for using array genotypes70.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [70] Mbatchou, 2021, Computationally efficient whole-genome regression for quantitative and binary traits, Nat. Genet. source

  • Probably not a substantial claim.

    Premisecitation

    It has been proposed that multiple receptors may contribute to Lp(a) clearance.

    “It has also been proposed that multiple receptors may contribute to Lp(a) clearance55.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] McCormick, 2019, Lipoprotein(a) catabolism: a case of multiple receptors, Pathology source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Statin usage has been associated with increased circulating Lp(a) levels.

    “Statin usage has been associated with increased circulating Lp(a) levels and we did find increased rates of this medication among pathogenic LDLR allele carriers.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Tsimikas, 2020, Statin therapy increases lipoprotein(a) levels, Eur. Heart J. source
33 of 33

  • The paper relies on this without support.

    HuH7 cells are a valid model of hepatocytes for Lp(a) uptake.

    “We performed a genome-scale CRISPR screen to functionally interrogate all potential Lp(a) uptake regulators in HuH7 cells.”

  • The paper relies on this without support.

    The single-donor commercial Lp(a) preparation is representative of circulating Lp(a) for receptor binding and cellular uptake.

    “We obtained Lp(a) from a commercial supplier that had been purified from single donor human plasma by ultracentrifugation and size exclusion chromatography and verified to lack detectable contaminating lipoproteins by agarose gel electrophoresis and total cholesterol staining.”

  • The paper relies on this without support.

    No prior study has systematically and unbiasedly interrogated all potential Lp(a) receptors in the same experimental context.

    “To date, no study has reported a systematic and unbiased functional interrogation of all potential Lp(a) receptors in the same experimental context.”

  • The paper relies on this without support.

    Lp(a) contains an LDL-like moiety with apolipoprotein B that can bind LDLR.

    “Lp(a) is comprised of an LDL-like moiety which includes the LDLR ligand apolipoprotein B covalently bound to a single apo(a) molecule via disulfide linkage.”

  • The paper relies on this without support.

    The CRISPR screen functionally tested all potential Lp(a) receptors simultaneously.

    “controlling for technical differences by functionally testing all potential Lp(a) receptors simultaneously.”
5 of 5

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Reyes-Soffer, 2021, Lipoprotein(a): a genetically determined, causal, and prevalent risk factor for atherosclerotic cardiovascular disease: a scientific statement from the American heart association, Arterioscler. Thromb. Vasc. Biol.

Cited by

Sorted by citations

Related

Metadata

Authors
Khan, T. G., Bragazzi Cunha, J., Raut, C., Burroughs, M., Vyas, H. S., Leix, K., Goonewardena, S. N., Smrcka, A. V., Speliotes, E. K., & Emmer, B. T.
Affiliations
University of Michigan (US)
Corresponding author
Emmer, Brian T.
ORCID
Venue
Atherosclerosis
Publisher
Elsevier BV
Published
2025-04
Volume
403
Pages
119174
ISSN
0021-9150 (ISSN-L)
DOI
10.1016/j.atherosclerosis.2025.119174
PMC
PMC12011201
OpenAlex
W4408733881
Semantic Scholar
766100bf0ed5a985c9eab9d77e8a19c97232fe4b
Cited by
6
References
93
Citations by year
2026: 4 · 2025: 2
FWCI
3.71
Type
journal article
Language
en
Open access
Licence
Locations
  • Atherosclerosis (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
Funders
  • University of Michigan
  • National Institutes of Health (R01-HL167733, R35-GM127303, K08-HL148552, R01-DK128871, R01-DK131787)
  • University of Michigan A Alfred Taubman Medical Research Institute
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
Keywords
lipoprotein(a), LDL receptor, idols, hepatocytes, calcific aortic stenosis, loss-of-function mutations, lipoprotein clearance, CRISPR screen

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

A language model drew the claims from the paper on 2026-11-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-11-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Cited sources are checked with a language model’s help (gpt-6-sol).

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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