Evidence map›Paper›PMID 40174266›Full record

ArticleAtherosclerosis2025

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

Taslima G Khan, Juliana Bragazzi Cunha, Chinmay Raut, Michael Burroughs, Hitarthi S Vyas, Kyle Leix, Sascha N Goonewardena, Alan V Smrcka, Elizabeth K Speliotes, Brian T Emmer

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Atherosclerosis, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Review
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

10 authors.

Taslima G KhanProgram in Chemical Biology, University of Michigan, Ann Arbor, MI, USA.
Juliana Bragazzi CunhaDivision of Hospital Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
Chinmay RautDivision of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA.
Michael BurroughsDepartment of Pharmacology, University of Michigan, Ann Arbor, MI, USA.
Hitarthi S VyasDivision of Hospital Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
Kyle LeixDivision of Hospital Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
Sascha N GoonewardenaDivision of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI, USA.
Alan V SmrckaDepartment of Pharmacology, University of Michigan, Ann Arbor, MI, USA.
Elizabeth K SpeliotesDivision of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA.
Brian T EmmerDivision of Hospital Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI, USA. Electronic address: bemmer@med.umich.edu.

Funding

University of Michigan Training Program in Genomic ScienceT32HG000040 · NHGRI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Sebastian Zoellner · 1995 to 2026
$16.4M
Understanding and Manipulating Phospholipase C and G Protein beta gamma subunit Signaling NetworksR35GM127303 · NIGMS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Alan V. Smrcka · 2018 to 2026
$4.8M
Integrative Polygenic Genetic Studies of Non-alcoholic Fatty Liver DiseaseR01DK131787 · NIDDK · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI SPELIOTES, ELIZABETH K · 2022 to 2025
$2.7M
Identification and Characterization of Loci Associated with Non-alcoholic Fatty Liver DiseaseR01DK128871 · NIDDK · WAKE FOREST UNIVERSITY HEALTH SCIENCES · PI ALLRED, NICHOLETTE D., SPELIOTES, ELIZABETH K · 2021 to 2024
$2.6M
Molecular Regulation of LDL Receptor ExpressionR01HL167733 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Brian T Emmer · 2024 to 2026
$1.9M
Modulation of Acute Lung Injury by Type I Interferon SignalingR01HL171013 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Brian T Emmer · 2025 to 2026
$1.4M
Cholesterol regulation by the cargo receptor SURF4K08HL148552 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI EMMER, BRIAN T · 2019 to 2023
$788k
CSRD VA I01 CX002560NHGRI NIH HHS T32 HG000040NHLBI NIH HHS K08 HL148552NHLBI NIH HHS R01 HL167733NHLBI NIH HHS R01 HL171013NIDDK NIH HHS R01 DK128871NIDDK NIH HHS R01 DK131787NIGMS NIH HHS R35 GM127303
6 · The paper itself

Abstract

BACKGROUND AND

aimsAn 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.

methodsWe 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.

resultsThe 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.

conclusionsOur findings support a central role for the LDL receptor in mediating Lp(a) uptake by hepatocytes.

Indexed as

Clustered Regularly Interspaced Short Palindromic RepeatsCRISPR-Cas SystemsHepatocytesLipoprotein(a)Receptors, LDLHumansUbiquitin-Protein LigasesUnited KingdomLDLR protein, humanLipoprotein(a)LPA protein, humanMYLIP protein, humanReceptors, LDLUbiquitin-Protein Ligases

Identifiers

PMID40174266
PMCPMC12011201

What Socratic holds

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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.