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Cited by 11Cholesterol and Lipid MetabolismLipoproteins and Cardiovascular HealthLipid metabolism and disorders

The DOI matches its Crossref record; 65 of the 65 references it cites were found in a registry or an index; 57 of the 90 sources its claims cite were checked for support.

Post-translational regulation of the low-density lipoprotein receptor provides new targets for cholesterol regulation

Open access
Aldworth, Harry, Hooper, Nigel M.·2024·Biochemical Society Transactions
DOI 10.1042/bst20230918PMC PMC10903450
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Abstract

The amount of the low-density lipoprotein receptor (LDLR) on the surface of hepatocytes is the primary determinant of plasma low-density lipoprotein (LDL)-cholesterol level. Although the synthesis and cellular trafficking of the LDLR have been well-documented, there is growing evidence of additional post-translational mechanisms that regulate or fine tune the surface availability of the LDLR, thus modulating its ability to bind and internalise LDL-cholesterol. Proprotein convertase subtilisin/kexin type 9 and the asialoglycoprotein receptor 1 both independently interact with the LDLR and direct it towards the lysosome for degradation. While ubiquitination by the E3 ligase inducible degrader of the LDLR also targets the receptor for lysosomal degradation, ubiquitination of the LDLR by a different E3 ligase, RNF130, redistributes the receptor away from the plasma membrane. The activity of the LDLR is also regulated by proteolysis. Proteolytic cleavage of the transmembrane region of the LDLR by γ-secretase destabilises the receptor, directing it to the lysosome for degradation. Shedding of the extracellular domain of the receptor by membrane-type 1 matrix metalloprotease and cleavage of the receptor in its LDL-binding domain by bone morphogenetic protein-1 reduces the ability of the LDLR to bind and internalise LDL-cholesterol at the cell surface. A better understanding of how the activity of the LDLR is regulated will not only unravel the complex biological mechanisms controlling LDL-cholesterol metabolism but also could help inform the development of alternative pharmacological intervention strategies for the treatment of hypercholesterolaemia.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that beyond well-documented synthesis and trafficking, the low-density lipoprotein receptor (LDLR) is controlled by a growing set of post-translational mechanisms that determine its surface availability, and that these mechanisms offer new pharmacological targets for lowering plasma LDL-cholesterol. It catalogues PCSK9, ASGR1, IDOL, RNF130, γ-secretase, MT1-MMP and BMP1 as regulators of LDLR, and discusses the therapeutic promise and pitfalls of targeting each.

Key findings

  • PCSK9 binds the LDLR EGF-like domain, prevents the endosomal conformational change needed for recycling, and directs the receptor to the lysosome; it can also bind newly synthesised LDLR at the trans-Golgi network and route it to the lysosome before it reaches the plasma membrane, giving two distinct degradative routes.
  • ASGR1 negatively regulates LDLR: knockdown increased total cellular LDLR and LDL uptake; loss-of-function ASGR1 mutations are associated with decreased non-HDL cholesterol and triglycerides and reduced atherosclerosis/CVD risk, and ASGR1 knockout had the same effect.
  • IDOL polyubiquitinates the LDLR cytosolic tail (recruited to the NPxY motif via its FERM domain, with UBE2D) to target it for lysosomal degradation; its expression is controlled by LxR/oxysterol rather than SREBP2, and the LxR–IDOL axis differentially regulates plasma LDL in primates versus mice (LxR activation in monkeys induced hepatic IDOL, reduced LDLR and raised plasma LDL, but did not change plasma LDL in mice).
  • RNF130 (GOLIATH) polyubiquitinates the LDLR but mainly redistributes it away from the cell surface as a reversible regulatory mechanism; antisense oligonucleotide disruption of *Rnf130* in mice increased hepatic LDLR abundance and decreased plasma LDL-cholesterol.
  • γ-secretase cleaves the LDLR transmembrane region, releasing a cytosolic domain degraded by the proteasome and destabilising the remaining receptor for lysosomal degradation; liver-selective γ-secretase inhibition ameliorated diet-induced dyslipidaemia in mice.
  • MT1-MMP cleaves the LDLR adjacent to the plasma membrane, releasing soluble sLDLR that retains the ligand-binding domain and can sequester LDL; hepatic MT1-MMP knockout increased cellular LDLR and reduced plasma cholesterol, while overexpression decreased LDLR, raised plasma cholesterol and increased atherosclerotic lesions.
  • BMP1 cleaves the LDLR within the ligand-binding domain between LA repeats 4 and 5 (between Gly192 and Asp193 in human LDLR), releasing a 36–40 kDa N-terminal fragment and retaining a 120 kDa C-terminal fragment at the plasma membrane; this reduces LDL binding affinity. The 120 kDa species was long misattributed to an immature LDLR form. Murine LDLR has Val in place of the critical Asp and is not cleaved by BMP1.

Methods

  • Narrative review article; no primary experimental data are reported. The authors synthesise published literature on transcriptional, post-transcriptional and post-translational regulation of the LDLR, with emphasis on post-translational mechanisms.
  • Evidence cited is drawn from cell, animal and human studies, including knockdown/knockout and overexpression experiments in mice and pigs, human primary hepatocytes, human liver and adrenal samples, human urine, and genetic association studies (e.g. ASGR1 variants, CCDC93 variant).
  • Two schematic figures summarise the mechanisms: Figure 1 depicts the post-translational regulatory pathways (A–I), and Figure 2 maps binding and cleavage sites on the LDLR domain structure.

Limitations

  • Stated by the paper: many proteins acting on the LDLR are promiscuous, with multiple other substrates, which "may pose difficulties for selective drug development"; and regulation of LDLR activity differs between primates and rodents, since IDOL and BMP1 act only on primate LDLR, so mouse studies using wild-type LDLR would not reveal BMP1's impact on LDL-cholesterol metabolism.
  • Stated by the paper: the exact γ-secretase cleavage site in the LDLR has yet to be experimentally confirmed, and the mechanics of the IDOL–USP8 ubiquitination system remain unclear, with contradictory evidence on whether USP8 promotes or prevents IDOL-mediated LDLR degradation.
  • Evident from the text: the review is largely descriptive and synthesises findings from heterogeneous model systems (cell lines, mice, monkeys, human samples) without a systematic search or quantitative synthesis, so the relative contribution of each mechanism to human LDL-cholesterol regulation is not established.

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

Integrity signals

Registry

Crossref · 10.1042/bst20230918

Cites

65 of 65 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

57 of 90 cited sources checked · 33 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Glycosylation within the LDLR ligand binding domain enhances the ligand binding affinity of the LDLR.

    “Glycosylation (both N-linked and O-linked) within the ligand binding domain has been shown to enhance the ligand binding affinity of the LDLR [19–21].”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [19] 2018, Site-specific O-glycosylation of members of the low-density lipoprotein receptor superfamily enhances ligand interactions, J. Biol. Chem. source

      The title in the Additions and Corrections item (p. 8349) states that site-specific O-glycosylation of LDL receptor superfamily members enhances ligand interactions. The available text does not establish that glycosylation occurs within LDLR’s ligand-binding domain or that both N-linked and O-linked glycosylation increase LDLR ligand-binding affinity. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
    • cites [20] 2014, Low density lipoprotein receptor class A repeats are O-glycosylated in linker regions, J. Biol. Chem. source

      The Abstract reports O-glycosylation in linker regions of the LDLR ligand-binding domain, and the Results identify potential N-glycosylation sites in the same region. The paper does not show that either type enhances ligand-binding affinity; it says the functional role of the O-glycans remains unclear. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [21] 1989, Effect of inhibiting N-glycosylation on the stability and binding activity of the low density lipoprotein receptor, J. Biol. Chem. source
  • Premisecitation

    The released intracellular cytosolic domain of LDLR is degraded by the proteasome.

    “The released intracellular cytosolic domain of LDLR is degraded by the proteasome (Figure 1G).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [52] 2018, γ-Secretase inhibition lowers plasma triglyceride-rich lipoproteins by stabilizing the LDL receptor, Cell Metab. source
  • Premisecitation

    Two zinc metalloproteases, MT1-MMP and BMP1, also cleave the LDLR.

    “In addition to the proteolytic cleavage of the LDLR by γ-secretase, two zinc metalloproteases also cleave the receptor, MT1-MMP and BMP1.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [56] 2022, Identification of amino acid residues in the MT-loop of MT1-MMP critical for its ability to cleave low-density lipoprotein receptor, Front. Cardiovasc. Med. source

      The Introduction and Results identify MT1-MMP as a zinc-dependent metalloproteinase that cleaves LDLR. Our copy does not identify BMP1 as another LDLR-cleaving protease, so it supports only the MT1-MMP part of the claim. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [37] 2019, Proteolysis of the low density lipoprotein receptor by bone morphogenetic protein-1 regulates cellular cholesterol uptake, Sci. Rep. source

      The Results section, “The zinc metalloprotease BMP1 cleaves the LDLR in its ligand binding domain” (page unavailable), confirms that BMP1 cleaves human LDLR. The Introduction also mentions γ-secretase-mediated cleavage, but the passages found in our copy do not identify MT1-MMP as an LDLR-cleaving protease (searched: MT1-MMP and membrane type 1 matrix metalloproteinase). (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Premisecitation

    In some patients, current treatments can cause a rebound in plasma cholesterol following withdrawal to higher than before treatment.

    “In addition, in some patients, these treatments can cause a rebound in plasma cholesterol following the withdrawal of the drug(s) to higher than that before treatment [13]”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [13] 2018, Discovery of a potent HMG-CoA reductase degrader that eliminates statin-induced reductase accumulation and lowers cholesterol, Nat. Commun. source

      The Introduction (page unavailable) says that stopping statins after long-term use may contribute to rebound effects in certain patients. It does not establish that plasma cholesterol rises above its pretreatment level, and it presents the rebound as a possibility rather than an observed result. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    Targeted lysosomal degradation of the LDLR in hepatocytes has been observed following proteolytic cleavage of the receptor by γ-secretase.

    “Targeted lysosomal degradation of the LDLR in hepatocytes has also been observed following proteolytic cleavage of the receptor by γ-secretase [52] (Figure 1G).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [52] 2018, γ-Secretase inhibition lowers plasma triglyceride-rich lipoproteins by stabilizing the LDL receptor, Cell Metab. source
  • It may state two separate claims as one. 42
  • Probably not a substantial claim. 17

  • It may state two separate claims as one.

    Premisecitation

    In mice, an LxR agonist induced Idol transcript levels in peripheral tissues but not in the liver and did not change plasma LDL levels.

    “In mice, an LxR agonist induced Idol transcript levels in peripheral tissues but not in the liver and did not change plasma LDL levels.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [50] 2014, The LXR-Idol axis differentially regulates plasma LDL levels in primates and mice, Cell Metab. source

      The Results section on tissue-specific regulation in mice reports that LXR agonist treatment did not change plasma LDL levels and altered LDLR protein in peripheral tissues but not the liver. The Results passages do not establish the claimed pattern of Idol transcript induction in peripheral tissues but not liver; the hepatocyte experiment reports induction in cultured mouse hepatocytes, a different condition. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation

    RNF130 decreases total LDLR levels, showing its polyubiquitination promotes targeted degradation of the receptor, but the more significant effect of RNF130 activity against the LDLR is subcellular redistribution of the receptor.

    “Although RNF130 decreases total LDLR levels showing its polyubiquitination promotes targeted degradation of the receptor, the more significant effect of RNF130 activity against the LDLR is the subcellular redistribution of the receptor (Figure 1F).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [51] 2023, RNF130 regulates LDLR availability and plasma LDL cholesterol levels, Circ. Res. source

      The Results (Fig. 2A, 2D–F) show that RNF130 ubiquitinates LDLR, reduces its total level, and has a proportionally greater effect at the cell surface, redistributing LDLR into intracellular compartments. The paper does not specify polyubiquitination, and it describes increased LDLR degradation as possible rather than establishing it as the mechanism of the reduction. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation

    Elevated blood LDL-cholesterol is a major risk factor for cardiovascular disease because LDL-cholesterol promotes atherosclerotic plaque formation.

    “elevated blood LDL-cholesterol (hypercholesterolaemia) is a major risk factor for this because LDL-cholesterol promotes the formation of atherosclerotic plaques on the walls of blood vessels, narrowing and eventually completely occluding blood flow [7].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [7] 2006, Pathogenesis of atherosclerosis, J. Am. Coll. Cardiol. source

      The Atherogenic Stimuli section identifies elevated plasma cholesterol as a major driver of atherosclerosis and LDL as an atherogenic lipoprotein. The Cellular Components section says persistent atherogenic stimuli can narrow the lumen and reduce blood flow. The citing sentence’s further claim that plaque formation eventually completely occludes flow is not supported: the paper describes thrombosis superimposed on plaques as the cause of the most severe acute consequences. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation

    ASGR1 interacts with the LDLR and directs it towards the lysosome for degradation.

    “Proprotein convertase subtilisin/kexin type 9 and the asialoglycoprotein receptor 1 both independently interact with the LDLR and direct it towards the lysosome for degradation.”
    • Also stated in: § ASGR1 · plain
      “As a glycoprotein also highly expressed in hepatocytes, the LDLR is targeted by ASGR1 (Figure 1D).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [42] 2021, Asialoglycoprotein receptor 1 is a novel PCSK9-independent ligand of liver LDLR cleaved by furin, J. Biol. Chem. source

      The Results report that ASGR1 forms a complex with LDLR independently of PCSK9, and the Discussion describes ASGR1-induced LDLR degradation (pages not available). The Discussion specifies endosomal/lysosomal degradation for PCSK9, but does not establish that ASGR1 directs LDLR to lysosomes. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation

    In monkeys, LxR activation induced hepatic IDOL expression, reduced LDLR levels and raised plasma LDL.

    “Whereas LxR activation in monkeys induced hepatic IDOL expression, reduced LDLR levels and raised plasma LDL, supporting IDOL inhibition as a potential strategy for lowering LDL-cholesterol in humans.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [50] 2014, The LXR-Idol axis differentially regulates plasma LDL levels in primates and mice, Cell Metab. source

  • It may state two separate claims as one.

    Premisecitation

    Secreted PCSK9 binds the EGF-like domain in the extracellular region of the LDLR and promotes internalisation of the receptor via clathrin-mediated endocytosis.

    “The secreted PCSK9 binds the EGF-like domain in the extracellular region of the LDLR (Figure 2) and promotes the internalisation of the receptor via clathrin-mediated endocytosis [38] (Figure 1C).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [38] 2007, Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation, J. Biol. Chem. source

      The Discussion reports that PCSK9 binds LDLR at EGF-A and that adding PCSK9 redistributes the receptor from the cell surface to endosomes and lysosomes. The paper says LDLR clusters in clathrin-coated pits, but it does not show that PCSK9 promotes clathrin-mediated internalisation; the Discussion instead describes PCSK9 as altering receptor trafficking after internalisation. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation

    When cellular cholesterol and oxysterol levels are elevated, oxysterol binds LxRs, causing a conformational change that promotes exchange of corepressor for co-activator and facilitates transcriptional activation of target genes such as IDOL.

    “When cellular cholesterol levels, and therefore oxysterol levels, are elevated, the oxysterol binds the LxRs, causing a conformational change that promotes the exchange of the corepressor for a co-activator, facilitating the transcriptional activation of target genes such as IDOL [49].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [49] 2009, LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor, Science source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation

    Proteolytic cleavage of the LDLR transmembrane region by γ-secretase destabilises the receptor and directs it to the lysosome for degradation.

    “Proteolytic cleavage of the transmembrane region of the LDLR by γ-secretase destabilises the receptor, directing it to the lysosome for degradation.”
    • Also stated in: § γ-secretase · plain
      “The lack of its cytosolic domain destabilises the LDLR and targets what is left of the receptor to the lysosome for degradation [52].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [52] 2018, γ-Secretase inhibition lowers plasma triglyceride-rich lipoproteins by stabilizing the LDL receptor, Cell Metab. source

  • It may state two separate claims as one.

    Premisecitation

    LDLR mRNA is regulated via multiple microRNAs, alternative splicing to produce non-functional LDLR protein, and regulation of LDLR mRNA decay.

    “At the post-transcriptional level, LDLR mRNA is regulated via several mechanisms including multiple microRNAs [30], alternative splicing to produce non-functional LDLR protein [31], and regulation of LDLR mRNA decay [32].”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [30] 2016, miRNA regulation of LDL-cholesterol metabolism, Biochim. Biophys. Acta source
    • cites [31] 2022, Posttranscriptional regulation of the human LDL receptor by the U2-Spliceosome, Circ. Res. source

      The Discussion (page unavailable) reports that intron 3 retention produces a truncated LDLR receptor, supporting the alternative-splicing mechanism attributed to citation [31]. It describes that receptor as “most probably non-functional,” whereas the citing sentence states non-functionality without qualification. The microRNA and mRNA-decay clauses have separate citations and are not judged here. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [32] 2022, Cold shock domain-containing protein E1 is a posttranscriptional regulator of the LDL receptor, Sci. Transl. Med. source

  • It may state two separate claims as one.

    Premisecitation

    RNF130, also known as GOLIATH, is an E3 ligase that has recently been implicated in LDLR regulation.

    “RNF130, also known as GOLIATH, another E3 ligase, has recently been implicated in LDLR regulation [51].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [51] 2023, RNF130 regulates LDLR availability and plasma LDL cholesterol levels, Circ. Res. source

  • It may state two separate claims as one.

    Premisecitation

    In the low pH endosome, PCSK9 remains bound to the LDLR, preventing the conformational change required for recycling, so the PCSK9-LDLR complex is directed to the lysosome where both proteins are degraded.

    “By remaining bound to the LDLR, PCSK9 prevents the conformational change of the LDLR that is required for its recycling back to the plasma membrane, therefore, inhibiting this recycling [38]. Instead, the PCSK9–LDLR complex is directed to the lysosome where both proteins are degraded (Figure 1C), thereby reducing the amount of LDLR in the cell [39].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [38] 2007, Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation, J. Biol. Chem. source

      The citation [39] is attached to the lysosomal-degradation sentence. The Abstract reports that LDLR is rerouted from the endosome to the lysosome and degraded, but the Discussion says the authors could not determine whether PCSK9 accompanies the receptor after cell entry. The claim that both proteins are degraded is therefore not supported by this paper. (LLM, conf=0.89)

      Experimental — accuracy not yet measured
    • cites [39] 2014, PCSK9 and LDLR degradation: regulatory mechanisms in circulation and in cells, Curr. Opin. Lipidol. source

  • It may state two separate claims as one.

    Premisecitation

    The lack of its cytosolic domain destabilises the LDLR and targets what is left of the receptor to the lysosome for degradation.

    “The lack of its cytosolic domain destabilises the LDLR and targets what is left of the receptor to the lysosome for degradation [52].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [52] 2018, γ-Secretase inhibition lowers plasma triglyceride-rich lipoproteins by stabilizing the LDL receptor, Cell Metab. source

  • It may state two separate claims as one.

    Premisecitation

    A coding variant in CCDC93 increases the stability of the protein and is associated with lower LDL-cholesterol, lower risk of myocardial infarction and of CVD mortality.

    “A coding variant in CCDC93 increases the stability of the protein and is associated with lower LDL-cholesterol, lower risk of myocardial infarction and of CVD mortality [26]”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [26] 2020, A common variant in CCDC93 protects against myocardial infarction and cardiovascular mortality by regulating endosomal trafficking of low-density lipoprotein receptor, Eur. Heart J. source

  • It may state two separate claims as one.

    Premisecitation

    Loss-of-function mutations in ASGR1 are associated with decreased levels of non-high-density lipoprotein cholesterol and triglycerides in blood plasma, resulting in a reduction in the risk of atherosclerosis and CVD.

    “Loss-of-function mutations in the ASGR1 gene are associated with decreased levels of non-high-density lipoprotein cholesterol and triglycerides in the blood plasma, resulting in a reduction in the risk of atherosclerosis and CVD [43].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [43] 2016, Variant ASGR1 associated with a reduced risk of coronary artery disease, N. Engl. J. Med. source

      Table 1 (Association of Sequence Variants with Non-HDL Cholesterol, p. 2134) reports lower non-HDL cholesterol and triglycerides in carriers of the ASGR1 del12 variant. The Abstract reports a lower risk of coronary artery disease, and the Discussion describes a possible atheroprotective effect. The paper does not establish that the lipid changes cause the risk reduction or measure a reduction in risk across CVD generally. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation

    Disruption of Rnf130 using antisense oligonucleotides in vivo in mice resulted in increased hepatic LDLR abundance and availability and decreased plasma LDL-cholesterol levels.

    “Disruption of Rnf130 using antisense oligonucleotides in vivo in mice resulted in increased hepatic LDLR abundance and availability and decreased plasma LDL-cholesterol levels [51]”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [51] 2023, RNF130 regulates LDLR availability and plasma LDL cholesterol levels, Circ. Res. source

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

    Premisecitation

    BMP1 is a metalloprotease with major roles in remodelling extracellular matrix proteins.

    “Like MT1-MMP, BMP1 is a metalloprotease with major roles in remodelling of extracellular matrix proteins, but BMP1 is a secreted protease rather than transmembrane [60].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [60] 2015, BMP-1/tolloid-like proteinases synchronize matrix assembly with growth factor activation to promote morphogenesis and tissue remodeling, Matrix Biol. source

  • It may state two separate claims as one.

    Premisecitation

    BMP1 is involved in cleaving the LDLR in human primary hepatocytes and in human liver and adrenal samples.

    “However, there is evidence that BMP1 is involved in cleaving the LDLR in human primary hepatocytes and in human liver and adrenal samples [37,61,63], and the 36–40 kDa N-terminal fragment is present in human urine, likely due to clearance from the blood plasma by the kidneys [61].”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [37] 2019, Proteolysis of the low density lipoprotein receptor by bone morphogenetic protein-1 regulates cellular cholesterol uptake, Sci. Rep. source

      The Results (no page given) report a cleaved LDLR fragment in human liver samples, and the Discussion says human LDLR is likely cleaved there by BMP1. But the Methods identify the studied liver-derived and adrenal cells as HepG2 and SW13 carcinoma cell lines, not primary human hepatocytes or human adrenal tissue samples. (LLM, conf=0.89)

      Experimental — accuracy not yet measured
    • cites [61] 2020, Bone morphogenetic protein 1 cleaves the linker region between ligand-binding repeats 4 and 5 of the LDL receptor and makes the LDL receptor non-functional, Hum. Mol. Genet. source
    • cites [63] 2023, Proteolysis of the low-density lipoprotein receptor in hepatocytes is mediated by BMP1 but not by other astacin proteases, FEBS Lett. source

  • It may state two separate claims as one.

    Premisecitation

    The site of cleavage in human LDLR by BMP1 is highly specific, between residues Gly192 and Asp193, with the Asp residue being crucial for cleavage.

    “The site of cleavage in human LDLR by BMP1 is highly specific, between residues Gly192 and Asp193, with the Asp residue being crucial for cleavage [37,61,63].”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [37] 2019, Proteolysis of the low density lipoprotein receptor by bone morphogenetic protein-1 regulates cellular cholesterol uptake, Sci. Rep. source

      The Results section, “The zinc metalloprotease BMP1 cleaves the LDLR in its ligand binding domain” (page unavailable), identifies the human LDLR cleavage bond as Gly171–Asp172, not Gly192–Asp193. The Results section, “Human but not murine LDLR is proteolytically cleaved by BMP1 in vivo” (page unavailable), supports the Asp-residue claim: replacing Asp172 with Val prevented cleavage. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [61] 2020, Bone morphogenetic protein 1 cleaves the linker region between ligand-binding repeats 4 and 5 of the LDL receptor and makes the LDL receptor non-functional, Hum. Mol. Genet. source
    • cites [63] 2023, Proteolysis of the low-density lipoprotein receptor in hepatocytes is mediated by BMP1 but not by other astacin proteases, FEBS Lett. source

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

    Premisecitation

    BMP1 is a secreted protease rather than transmembrane.

    “Like MT1-MMP, BMP1 is a metalloprotease with major roles in remodelling of extracellular matrix proteins, but BMP1 is a secreted protease rather than transmembrane [60].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [60] 2015, BMP-1/tolloid-like proteinases synchronize matrix assembly with growth factor activation to promote morphogenesis and tissue remodeling, Matrix Biol. source

  • It may state two separate claims as one.

    Premisecitation

    BMP1-mediated cleavage of LDLR releases a small N-terminal fragment of 36-40 kDa and retains a C-terminal fragment of 120 kDa in the plasma membrane.

    “The BMP1-mediated cleavage of LDLR releases a small N-terminal fragment of 36–40 kDa and retains a C-terminal fragment of 120 kDa in the plasma membrane (Figure 1I) [37,61].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [37] 2019, Proteolysis of the low density lipoprotein receptor by bone morphogenetic protein-1 regulates cellular cholesterol uptake, Sci. Rep. source
    • cites [61] 2020, Bone morphogenetic protein 1 cleaves the linker region between ligand-binding repeats 4 and 5 of the LDL receptor and makes the LDL receptor non-functional, Hum. Mol. Genet. source

  • It may state two separate claims as one.

    Interpretationcitation

    Inhibition of MT1-MMP is a promising therapeutic target to increase hepatic LDLR levels, lower plasma LDL-cholesterol, and reduce the risk of cancer metastasis and invasion.

    “Thus, inhibition of MT1-MMP is a promising therapeutic target to not only increase hepatic LDLR levels and lower plasma LDL-cholesterol, but also to reduce the risk of cancer metastasis and invasion [58].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [58] 2021, Membrane type 1 matrix metalloproteinase promotes LDL receptor shedding and accelerates the development of atherosclerosis, Nat. Commun. source

  • It may state two separate claims as one.

    Premisecitation

    MT1-MMP is highly expressed in various types of cancer cells and promotes cancer metastasis and angiogenesis.

    “MT1-MMP is highly expressed in various types of cancer cells and promotes cancer metastasis and angiogenesis [57,59].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [57] 2015, Membrane-type matrix metalloproteinases: their functions and regulations, Matrix Biol. source
    • cites [59] 2017, Matrix metalloproteinase collagenolysis in health and disease, Biochim. Biophys. Acta Mol. Cell Res. source

      Section 5, “The role of collagen catabolism in disease” (page unavailable), says MT1-MMP appears to play a significant role in tumor metastasis and reports a correlation between its collagenolysis and metastasis in vivo. It does not say MT1-MMP is highly expressed across various cancer-cell types or that it promotes angiogenesis; its discussion of endothelial-cell migration does not establish the latter claim. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation

    Knockout of hepatic MT1-MMP leads to an increase in cellular LDLR levels and a reduction in plasma cholesterol.

    “Recent research has identified MT1-MMP as a regulator of LDLR cell surface availability, with knockout of hepatic MT1-MMP leading to an increase in cellular LDLR levels and a reduction in plasma cholesterol, and overexpression of MT1-MMP decreasing total LDLR levels, increasing plasma cholesterol levels and increasing atherosclerotic lesions [58].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [58] 2021, Membrane type 1 matrix metalloproteinase promotes LDL receptor shedding and accelerates the development of atherosclerosis, Nat. Commun. source

  • It may state two separate claims as one.

    Premisecitation

    The 120 kDa LDLR species is primarily a BMP1 cleavage product present at the cell surface and not an intracellular immature form of the receptor.

    “However, recent research has shown that this 120 kDa species is in fact primarily a BMP1 cleavage product present at the cell surface and not an intracellular immature form of the receptor [63].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [63] 2023, Proteolysis of the low-density lipoprotein receptor in hepatocytes is mediated by BMP1 but not by other astacin proteases, FEBS Lett. source

      The Results section reports that the 130 kDa band in primary hepatocytes is predominantly a BMP1-cleaved LDLR fragment at the cell surface, rather than an intracellular precursor. The paper also describes a 120 kDa BMP1-generated fragment, but the experiment distinguishing a cell-surface cleavage product from an immature receptor specifically concerns the 130 kDa band. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

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

    Premisecitation

    MT1-MMP is a transmembrane protease with major and well-established functions in remodelling extracellular matrix proteins.

    “MT1-MMP is a transmembrane protease that has major and well-established functions in the remodelling of extracellular matrix proteins [57].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [57] 2015, Membrane-type matrix metalloproteinases: their functions and regulations, Matrix Biol. source

  • It may state two separate claims as one.

    Premisecitation

    Overexpression of MT1-MMP decreases total LDLR levels, increases plasma cholesterol levels, and increases atherosclerotic lesions.

    “Recent research has identified MT1-MMP as a regulator of LDLR cell surface availability, with knockout of hepatic MT1-MMP leading to an increase in cellular LDLR levels and a reduction in plasma cholesterol, and overexpression of MT1-MMP decreasing total LDLR levels, increasing plasma cholesterol levels and increasing atherosclerotic lesions [58].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [58] 2021, Membrane type 1 matrix metalloproteinase promotes LDL receptor shedding and accelerates the development of atherosclerosis, Nat. Commun. source

  • Probably not a substantial claim. It may be too vague to check against evidence.

    Interpretationreasoning

    There is still a need to develop alternative drugs to reduce LDL-cholesterol.

    “Thus, there is still a need to develop alternative drugs to reduce LDL-cholesterol.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    PCSK9 is under the regulation of SREBP2 and its expression is responsive to the cellular cholesterol level.

    “Like the LDLR, PCSK9 is under the regulation of SREBP2 and its expression is, therefore, also responsive to the cellular cholesterol level [27].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] 2002, SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver, J. Clin. Invest. source

  • It may state two separate claims as one.

    Premisereasoning

    IDOL expression is sensitive to the cholesterol status of the cell and is regulated by LxRs, not via SREBP2.

    “Like the expression of the LDLR and PCSK9, the expression of IDOL is also sensitive to the cholesterol status of the cell, although not via SREBP2. Instead, IDOL expression is regulated by the liver x receptor nuclear receptor family of proteins (LxRs).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    The LDLR ligand binding domain recognises apolipoprotein B100 and, to a lower affinity, apolipoprotein E.

    “This ligand binding domain recognises the protein component of LDL particles, apolipoprotein B100, and, to a lower affinity, apolipoprotein E which is present in very low-density lipoprotein particles and chylomicrons [17,18].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [17] 2008, Apolipoprotein E isoform-specific binding to the low-density lipoprotein receptor, Anal. Biochem. source
    • cites [18] 2005, The LDL receptor: how acid pulls the trigger, Trends Biochem. Sci. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisereasoning

    To remove autoinhibition, most γ-secretase substrates are cleaved extracellularly, leaving a short extracellular tail on the transmembrane region which nicastrin binds to and which then exposes the γ-secretase active site.

    “To remove this autoinhibition, most substrates are cleaved extracellularly, leaving a short extracellular tail on the transmembrane region which nicastrin binds to and which then exposes the γ-secretase active site, such as”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisereasoning

    IDOL decreases the surface levels of the LDLR, thereby decreasing cellular uptake of LDL-cholesterol.

    “but what is clear is that IDOL decreases the surface levels of the LDLR, thereby decreasing cellular uptake of LDL-cholesterol.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    The LDLR binds LDL via an extracellular ligand binding domain composed of 7 cysteine-rich LDLR type A repeats.

    “The LDLR binds LDL via an extracellular ligand binding domain composed of 7 cysteine-rich LDLR type A (LA) repeats, each separated by a short linker of a few amino acids [16] (Figure 2).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] 1999, Structural independence of ligand-binding modules five and six of the LDL receptor, Biochemistry source

  • It may state two separate claims as one.

    Premisecitation

    Knockdown of ASGR1 increased the total amount of LDLR in the cell and increased LDL uptake, showing that ASGR1 normally negatively regulates LDLR availability and LDL uptake.

    “Knockdown of ASGR1 increased the total amount of LDLR in the cell and increased the uptake of LDL, showing that ASGR1 normally negatively regulates LDLR availability and, as a result, LDL uptake [42].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] 2021, Asialoglycoprotein receptor 1 is a novel PCSK9-independent ligand of liver LDLR cleaved by furin, J. Biol. Chem. source

  • It may state two separate claims as one.

    Premisecitation

    When cellular cholesterol is depleted, the SCAP-SREBP2 complex is transported to the Golgi where SREBP2 is activated and released into the cytosol, translocates to the nucleus and up-regulates target genes including LDLR.

    “When cellular cholesterol is depleted, the SCAP–SREBP2 complex is transported to the Golgi where SREBP2 is activated and released into the cytosol from where it translocates to the nucleus and up-regulates the expression of target genes, including LDLR.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    Silencing of ASGR1 may provide a novel approach to reduce plasma LDL-cholesterol levels and protect against atherosclerosis.

    “Together, this shows the role of ASGR1 in the post-translational regulation of the LDLR, and suggests that silencing of ASGR1 may provide a novel approach to reduce plasma LDL-cholesterol levels and thus protect against the formation and progression of atherosclerosis.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    LDLR expression is under the control of SREBP2, which is regulated by cellular cholesterol status via interaction with SCAP.

    “The expression of the LDLR is under the control of the transcription factor sterol response element binding protein 2 (SREBP2), which is regulated by cellular cholesterol status via interaction with a cholesterol-sensing protein, SREBP cleavage-activating protein (SCAP) [27].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] 2002, SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver, J. Clin. Invest. source

  • Probably not a substantial claim. It may be too vague to check against evidence.

    Interpretationreasoning

    A better understanding of how LDLR activity is regulated could help inform the development of alternative pharmacological intervention strategies for hypercholesterolaemia.

    “A better understanding of how the activity of the LDLR is regulated will not only unravel the complex biological mechanisms controlling LDL-cholesterol metabolism but also could help inform the development of alternative pharmacological intervention strategies for the treatment of hypercholesterolaemia.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    RAP binds to the LDLR ligand binding domain in the ER to promote transport along the secretory pathway towards the plasma membrane, and this association reduces the affinity of the receptor for LDL.

    “RAP binds to the ligand binding domain of the LDLR (Figure 2) in the ER [35] to promote transport along the secretory pathway towards the plasma membrane (Figure 1A), with this association between RAP and the LDLR also reducing the affinity of the receptor for LDL [36].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [35] 2006, Structure of an LDLR-RAP complex reveals a general mode for ligand recognition by lipoprotein receptors, Mol. Cell source
    • cites [36] 1998, RAP, a novel type of ER chaperone, Trends Cell Biol. source

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

    Premisenone given

    Normally, the γ-secretase complex is autoinhibited by the nicastrin subunit, where nicastrin binds and blocks the active site of the catalytic presenilin subunit.

    “Normally, the γ-secretase complex is autoinhibited by the nicastrin subunit, where nicastrin binds and blocks the active site of the catalytic presenilin subunit, inhibiting its activity.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Contradictory evidence suggests that USP8 may prevent IDOL-mediated LDLR degradation, with co-expression of IDOL and USP8 increasing total cellular LDLR.

    “However, there is also contradictory evidence suggesting that the action of USP8 may prevent IDOL-mediated LDLR degradation, with co-expression of IDOL and USP8 resulting in an increase in total cellular LDLR [47].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] 2013, The LXR-IDOL axis defines a clathrin-, caveolae-, and dynamin-independent endocytic route for LDLR internalization and lysosomal degradation, J. Lipid Res. source

      Checked before — its earlier verdict is held back until a new check runs.

  • It may state two separate claims as one.

    Premisecitation

    PCSK9 can bind newly synthesised LDLR at the trans-Golgi network and target it directly to the lysosome before it reaches the plasma membrane; disruption of this intracellular transport increases cell surface LDLR.

    “In addition, PCSK9 can bind newly synthesised LDLR at the trans-Golgi network and target it directly to the lysosome before it has reached the plasma membrane (Figure 1C), with disruption of this intracellular transport between the trans-Golgi network and lysosome resulting in an increase in cell surface LDLR [40].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [40] 2009, Dissection of the endogenous cellular pathways of PCSK9-induced low density lipoprotein receptor degradation: evidence for an intracellular route, J. Biol. Chem. source

  • It may state two separate claims as one.

    Premisecitation

    The nicastrin subunit of γ-secretase binds to the LDLR and recruits the rest of the γ-secretase complex, resulting in cleavage of the LDLR.

    “The nicastrin subunit of γ-secretase binds to the LDLR and recruits the rest of the γ-secretase complex, resulting in the cleavage of the LDLR”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] 2018, γ-Secretase inhibition lowers plasma triglyceride-rich lipoproteins by stabilizing the LDL receptor, Cell Metab. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Interpretationcitation

    γ-secretase normally cleaves substrates within its transmembrane domain, so this is likely also the case for the LDLR, though the exact cleavage site has yet to be experimentally confirmed.

    “γ-secretase normally cleaves substrates within its transmembrane domain so this is likely also the case for the LDLR (Figure 2), though the exact cleavage site has yet to be experimentally confirmed”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] 2003, Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-Secretase complex, Neuron source

  • It may state two separate claims as one.

    Premisecitation

    When cellular cholesterol is elevated, the SCAP-SREBP2 complex cannot be transported to the Golgi and SREBP2 is sequestered at the ER membrane as an inactive precursor.

    “When cellular cholesterol is elevated, the SCAP–SREBP2 complex cannot be transported to the Golgi and so SREBP2 is sequestered at the membrane of the endoplasmic reticulum (ER) as an inactive precursor [28,29].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [28] 2004, Direct binding of cholesterol to the purified membrane region of SCAP: mechanism for a sterol-sensing domain, Mol. Cell source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [29] 2005, Insig required for sterol-mediated inhibition of Scap/SREBP binding to COPII proteins in vitro, J. Biol. Chem. source

      Checked before — its earlier verdict is held back until a new check runs.

  • It may state two separate claims as one.

    Premisecitation

    IDOL is recruited to the NPxY motif in the LDLR intracellular domain via its FERM domain and catalyses polyubiquitination of the LDLR cytosolic tail.

    “IDOL is recruited to the NPxY motif in the intracellular domain of the LDLR (Figure 2) via its FERM domain and catalyses polyubiquitination of the LDLR cytosolic tail [46].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [46] 2011, FERM-dependent E3 ligase recognition is a conserved mechanism for targeted degradation of lipoprotein receptors, Proc. Natl Acad. Sci. U.S.A. source

  • It may state two separate claims as one.

    Premisecitation

    The 36-40 kDa N-terminal fragment is present in human urine, likely due to clearance from the blood plasma by the kidneys.

    “However, there is evidence that BMP1 is involved in cleaving the LDLR in human primary hepatocytes and in human liver and adrenal samples [37,61,63], and the 36–40 kDa N-terminal fragment is present in human urine, likely due to clearance from the blood plasma by the kidneys [61].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] 2020, Bone morphogenetic protein 1 cleaves the linker region between ligand-binding repeats 4 and 5 of the LDL receptor and makes the LDL receptor non-functional, Hum. Mol. Genet. source

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

    Premisenone given

    Regulation of LDLR activity differs between primates and rodents, with IDOL and BMP1 only acting on primate LDLR.

    “Also, regulation of LDLR activity differs between primates and rodents (IDOL and BMP1 only act on primate LDLR).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. It may be too vague to check against evidence.

    Interpretationreasoning

    Many proteins involved in post-translational processing of the LDLR could be utilised to develop new, additional therapeutics for the treatment of cholesterol dysregulation.

    “Indeed, as mentioned above, there are already drugs developed that target the PCSK9-mediated degradation of the LDLR, but this is just one of many proteins that are involved in the post-translational processing of the receptor that could be utilised to develop new, additional therapeutics for the treatment of cholesterol dysregulation.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Drugs have been developed that target the PCSK9-mediated degradation of the LDLR.

    “Indeed, as mentioned above, there are already drugs developed that target the PCSK9-mediated degradation of the LDLR, but this is just one of many proteins that are involved in the post-translational processing of the receptor that could be utilised to develop new, additional therapeutics for the treatment of cholesterol dysregulation.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    MT1-MMP mediated cleavage of the LDLR provides a two-fold regulatory mechanism: reducing full-length LDLR at the cell surface and generating a soluble receptor that can sequester LDL in the extracellular space, preventing its interaction with uncleaved receptor on the cell surface.

    “Therefore, the MT1-MMP mediated cleavage of the LDLR provides a two-fold regulatory mechanism; reducing the amount of full-length LDLR at the cell surface, and generating a soluble form of the receptor that can sequester the LDL in the extracellular space, preventing its interaction with any uncleaved receptor on the cell surface.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper may give no reason why it holds.

    Premisenone given

    The LDLR is a major point of regulation in cholesterol homeostasis.

    “The LDLR is a major point of regulation in cholesterol homeostasis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper may give no reason why it holds.

    Interpretationnone given

    Many of the proteins that act on the LDLR are promiscuous, having multiple other substrates that may pose difficulties for selective drug development.

    “Many of the proteins that act on the LDLR are promiscuous, having multiple other substrates that may pose difficulties for selective drug development.”
    Quote in the paperNot a substantial claim
53 of 53

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Trans-Golgi PCSK9 route is assigned the wrong figure panel

    Minor

    The text cites Figure 1C for PCSK9 targeting newly synthesised LDLR from the trans-Golgi to the lysosome, but the figure legend assigns that route to panel C'. Panel C describes extracellular PCSK9 binding.

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Metadata

Authors
Aldworth, H., & Hooper, N. M.
Affiliations
University of Manchester (GB)
Corresponding author
Hooper, Nigel M.
ORCID
Hooper, Nigel M.
Venue
Biochemical Society Transactions
Publisher
Portland Press Ltd.
Published
2024-02-08
Volume
52
Issue
1
Pages
431-440
ISSN
  • 0300-5127 (ISSN-L)
  • 1470-8752
DOI
10.1042/bst20230918
PMC
PMC10903450
OpenAlex
W4391653796
Cited by
11
References
65
Citations by year
2026: 5 · 2025: 6
FWCI
1.78
Type
journal article
Language
en
Open access
Licence
Locations
  • Biochemical Society Transactions (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Explorer (The University of Manchester) (submittedVersion, cc-by)
Funders
Directorate for Biological Sciences
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
Keywords
LDL receptor, post-translational regulation, LDL cholesterol metabolism, hypercholesterolemia, PCSK9, ASGR1, ubiquitination, E3 ubiquitin ligase, gamma-secretase, MT1-MMP, BMP1, receptor proteolysis, receptor internalization, lysosomal degradation, hepatocytes
MeSH terms
Cholesterol, Cholesterol, LDL, Receptors, LDL, Hepatocytes, Ubiquitin-Protein Ligases, Proteolysis

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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 2026-11-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

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