The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms

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

Hepatic silencing of Asgr1 in mice proposed that ASGR1 attenuates hepatic SREBP2 signaling and reduces PCSK9 levels.

“This was similarly observed in a study employing hepatic silencing of Asgr1 in mice [87], which proposed that ASGR1 attenuates hepatic SREBP2 signaling and reduces PCSK9 levels.”

• cites [87] Xu, 2021, Hypomorphic ASGR1 modulates lipid homeostasis via INSIG1-mediated SREBP signaling suppression, JCI Insight sourceDisputed

  The Results section on SREBP activation reports that ASGR1-deficient mouse livers had lower nuclear SREBP2, and the LDL-uptake Results section reports lower PCSK9 under ASGR1-deficient conditions. The Results section on restoring ASGR1 expression reports the opposite effect: SREBP1/2 and PCSK9 increased. The cited paper therefore attributes attenuation to loss of ASGR1, not to ASGR1 itself; our copy provides no page numbers for these passages. (LLM, conf=0.90)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

It may state two separate claims as one.

Pigs lacking ASGR1 showed a decrease in non-HDL cholesterol in the circulation and a reduction in atherosclerotic lesions after a high-fat high-cholesterol diet, with no apparent liver damage.

“Like in human carriers of ASGR1 inactivating mutations, pigs lacking ASGR1 showed a decrease in non-HDL cholesterol in the circulation and a reduction in atherosclerotic lesions after a high-fat high-cholesterol diet, with no apparent liver damage [85,86].”

• cites [85] Xie, 2021, Deficiency of ASGR1 in pigs recapitulates reduced risk factor for cardiovascular disease in humans, PLoS Genet. sourceDisputed

  The Results section on HFHC feeding reports lower non-HDL cholesterol and fewer atherosclerotic lesions in ASGR1-deficient pigs than in controls. But the Results section titled “Mild to moderate liver injury was observed in ASGR1-deficient pigs” reports hepatic inflammation and fibrosis, directly contradicting the claim of no apparent liver damage. The reported liver histology was from 24-month-old pigs on a normal diet, not the HFHC-fed cohort. (LLM, conf=0.88)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured
• cites [86] Yin, 2024, ASGR1 is a promising target for lipid reduction in pigs with PON2 as its inhibitor, iScience sourcePartly supported

  The Results report reduced serum lipids, including non-HDL cholesterol, in ASGR1+/− pigs and no apparent hepatic inflammation or liver damage. But the Methods say the pigs had normal food, and the paper does not report reduced atherosclerotic lesions in ASGR1-deficient pigs after a high-fat, high-cholesterol diet. Its Introduction discusses lesions after a high-fat diet in mice lacking PON2, not these pigs. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

γ-secretase promotes ectodomain shedding of LDLR, decreasing LDLR.

“γ-secretase Promotes ectodomain shedding of LDLR ↓ [110-112, 114]”

• cites [110] De Strooper, 2003, Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-Secretase complex, Neuron sourceNot checked — no full text of the source
• cites [111] Tamboli, 2008, Loss of gamma-secretase function impairs endocytosis of lipoprotein particles and membrane cholesterol homeostasis, J. Neurosci. sourcePartly supported

  In “Inhibition of γ-secretase impairs endocytosis of lipoprotein receptors” (page unavailable), reexpression of PS1 decreased LDLR at the cell surface, supporting an effect on surface LDLR. The paper attributes that effect to LDLR internalization and does not report that γ-secretase promotes LDLR ectodomain shedding. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [112] Tveten, 2013, PCSK9-mediated degradation of the LDL receptor generates a 17 kDa C-terminal LDL receptor fragment, J. Lipid Res. sourceDisputed

  The Discussion reports that the LDLR fragment was generated during PCSK9-mediated degradation even in the presence of the γ-secretase inhibitor DAPT. The ‘Intracellular degradation of a Class 5 mutant LDLR’ section says ectodomain cleavage precedes γ-secretase cleavage and implicates cysteine cathepsins in generating the fragment. The paper therefore does not present γ-secretase as promoting LDLR ectodomain shedding. (LLM, conf=0.85)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured
• cites [114] Kim, 2018, Gamma-secretase inhibition lowers plasma triglyceride-rich lipoproteins by stabilizing the LDL receptor, Cell Metabol. sourcePartly supported

  The Results section (“γ-secretase regulates LDLR protein stability”) reports that γ-secretase-mediated cleavage destabilizes LDLR and promotes its lysosomal degradation. But the Discussion describes this as intramembrane proteolysis and says LDLR may be shed by other secretases before γ-secretase cleavage; it does not establish that γ-secretase promotes ectodomain shedding. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

miR-191, miR-221-5p, miR-222, miR-224, miR-342-5p, miR-363-5p, miR-483, miR-520d, miR-609, miR-765, miR-3165, and miR-1908-5p inhibit expression of PCSK9, increasing LDLR.

“miR-191, miR-221-5p, miR-222, miR-224, miR-342-5p, miR-363-5p, miR-483, miR-520d, miR-609, miR-765, miR-3165, miR-1908-5p Inhibit expression of PCSK9 ↑ [50-55]”

• cites [50] Salerno, 2020, LDL receptor pathway regulation by miR-224 and miR-520d, Front Cardiovasc. Med. sourcePartly supported

  The Introduction and Results report that miR-224 and miR-520d repress PCSK9 and increase LDLR expression in hepatic cells. The Discussion also identifies miR-191 and miR-222 as PCSK9 regulators, but our copy does not support the claimed PCSK9-to-LDLR effect for them or address the other listed miRNAs. Page numbers are not provided in our copy. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [51] Naeli, 2017, Post-transcriptional Regulation of PCSK9 by miR-191, miR-222, and miR-224, Front. Genet. sourcePartly supported

  The Results section reports that overexpressing miR-191, miR-222, and miR-224 reduced PCSK9 mRNA in HepG2 cells. The paper does not establish PCSK9 inhibition for the other listed miRNAs; the Discussion describes miR-221 only as a possibility. It identifies PCSK9 as a negative regulator of LDLR but does not report an increase in LDLR after miRNA overexpression. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [52] Bai, 2017, A retrospective study of NENs and miR-224 promotes apoptosis of BON-1 cells by targeting PCSK9 inhibition, Oncotarget sourcePartly supported

  The Results section (‘PCSK9 is the direct target of miR-224,’ Figure 4) shows that miR-224 reduces PCSK9 expression in BON-1 cells. The paper does not establish PCSK9 inhibition for the other listed miRNAs, and although the Discussion says PCSK9 degrades the LDL receptor, it does not report an increase in LDLR following miR-224 treatment. Page numbers are unavailable in our copy. (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites [53] Dong, 2020, microRNA-483 ameliorates hypercholesterolemia by inhibiting PCSK9 production, JCI Insight sourcePartly supported

  The Results section ('miRs targeting Pcsk9 alleviated hyperlipidemia and atherosclerosis'; page not provided) reports that miR-191, miR-222, miR-224, and miR-483 reduced activity of a PCSK9 3′-UTR reporter. It documents reduced PCSK9 and increased LDLR expression for miR-483, but does not establish those effects for every miRNA in the citing list; the other listed miRNAs are not addressed in these passages. (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites [54] van Solingen, 2021, High-throughput screening identifies MicroRNAs regulating human PCSK9 and hepatic low-density lipoprotein receptor expression, Front Cardiovasc. Med. sourcePartly supported

  The Introduction names miR-191, miR-222, miR-224, miR-483, and miR-520d as reported PCSK9 inhibitors, while the Discussion identifies miR-221-5p, miR-342-5p, miR-363-5p, miR-609, miR-765, and miR-3165 as inhibitors found in this study. The Results and Discussion report increased LDLR expression for only some of these miRNAs, not the entire list. Our copy does not identify miR-1908-5p as a PCSK9 inhibitor. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [55] Beehler, 2021, A common polymorphism in the FADS1 locus links miR1908 to low-density lipoprotein cholesterol through BMP1, Arterioscler. Thromb. Vasc. Biol. sourceDisputed

  In ‘Identification of Potential Target Genes of miR-1908-5p’ (page unavailable), the paper reports that total LDLR protein remained unchanged after miR-1908-5p treatment, contrary to the claimed increase in LDLR. Its conclusion instead attributes improved LDLR function to reduced TGFB1, BMP1, and LDLR cleavage; it does not report PCSK9 inhibition or test the other listed miRNAs. (LLM, conf=0.83)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

It may state two separate claims as one.

PCSK9 is a secreted protein that binds to the LDLR ectodomain and promotes its degradation.

“One of the most well-documented mechanisms involves PCSK9 [13][14][15].PCSK9 binds to the ectodomain of LDLR at the cell surface and is internalized together with the receptor.”

• cites [13] Park, 2004, Post-transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver, J. Biol. Chem. sourcePartly supported

  The Results and Discussion (page unavailable) report that PCSK9 overexpression reduces LDLR protein, supporting the degradation part of the claim. But the Discussion leaves open whether PCSK9 acts as a secreted protein and says its effect appears to occur before LDLR internalization; it does not establish ectodomain binding or co-internalization. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [14] Tavori, 2015, On the function and homeostasis of PCSK9: reciprocal interaction with LDLR and additional lipid effects, Atherosclerosis sourceSupported
• cites [15] Seidah, 2014, PCSK9: a key modulator of cardiovascular health, Circ. Res. sourceSupported

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

Therapeutic strategies targeting PCSK9, such as monoclonal antibodies and CRISPR/Cas9-mediated hepatic genome editing, are highly effective in lowering circulating LDL cholesterol and reducing the burden of cardiovascular disease.

“Accordingly, therapeutic strategies that target PCSK (e.g.monoclonal antibodies, CRISPR/Cas9-mediated hepatic genome editing) are highly effective in lowering circulating LDL cholesterol and reducing the burden of cardiovascular disease [15].”

• cites [15] Seidah, 2014, PCSK9: a key modulator of cardiovascular health, Circ. Res. sourcePartly supported

  The PCSK9-Based Therapies and Safety Considerations section reports substantial LDL-cholesterol reductions with PCSK9 monoclonal antibodies. The Conclusions section says long-term studies were still needed to establish whether PCSK9 inhibition reduces cardiovascular disease risk. Our copy does not describe CRISPR/Cas9-mediated hepatic genome editing, so it does not support that example or the claim that these therapies had already reduced cardiovascular disease burden. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

ZFP36L1 and ZFP36L2 influence LDLR mRNA stability, operate in an ERK-dependent manner, bind to the 3′UTR of LDLR mRNA, and promote its destabilization.

“Using a proteomics-based approach, two additional RBPs, ZFP36L1 and ZFP36L2, that influence LDLR mRNA stability were identified [30].These proteins operate in an ERK-dependent manner, binding to the 3′UTR of LDLR mRNA and promoting its destabilization.”

• cites [30] Adachi, 2014, ZFP36L1 and ZFP36L2 control LDLR mRNA stability via the ERK-RSK pathway, Nucleic Acids Res. sourceSupported

It may state two separate claims as one.

Mice lacking Idol have a beneficial metabolic and plasma lipid profile, yet the effect on hepatic LDLR was limited.

“Mice lacking Idol have a beneficial metabolic and plasma lipid profile, yet the effect on hepatic LDLR was limited.”

• cites [73] van Loon, 2018, Inactivation of the E3 ubiquitin ligase IDOL attenuates diet-induced obesity and metabolic dysfunction in mice, Arterioscler. Thromb. Vasc. Biol. sourceSupported
• cites [74] Lee, 2019, IDOL regulates systemic energy balance through control of neuronal VLDLR expression, Nat. Metab. sourcePartly supported

  The Results section ('Global IDOL-knockout mice are protected from diet-induced metabolic dysfunction'; page unavailable) reports reduced adiposity and improved glucose and insulin tolerance in IDOL-deficient mice. The Discussion (page unavailable) says hepatic IDOL and LDLR are not required for this metabolic phenotype. Our copy does not establish a beneficial plasma lipid profile or show that the effect of Idol deletion on hepatic LDLR expression was limited; those are different claims from a limited role for hepatic LDLR in the phenotype. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

IDOL is an E3 ubiquitin ligase that ubiquitylates a conserved sequence within the intracellular tail of the LDLR, leading to its subsequent lysosomal degradation.

“Subsequent work demonstrated that IDOL is an E3 ubiquitin ligase that ubiquitylates a conserved sequence within the intracellular tail of the LDLR [62,65,66], leading to its subsequent lysosomal degradation.”

• cites [62] Zelcer, 2009, LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor, Science sourceSupported
• cites [65] Sorrentino, 2011, Distinct functional domains contribute to degradation of the low density lipoprotein receptor (LDLR) by the E3 ubiquitin ligase inducible Degrader of the LDLR (IDOL), J. Biol. Chem. sourcePartly supported

  The Results identify a conserved region of the LDLR intracellular tail, including Phe-823 and Asp-824, as important for interaction with IDOL and IDOL-mediated degradation. The Discussion reports that IDOL promotes LDLR ubiquitination and proposes that this directs the receptor toward lysosomal degradation. Neither passage establishes that the conserved sequence itself is the site of ubiquitination. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [66] Calkin, 2011, FERM-dependent E3 ligase recognition is a conserved mechanism for targeted degradation of lipoprotein receptors, Proc. Natl. Acad. Sci. U.S.A. sourceNot checked — no full text of the source

It may state two separate claims as one.

Knockdown of hnRNP D, hnRNP I, and KSRP led to an increase of over 50% in LDLR mRNA levels and a concomitant 40% increase in LDLR protein abundance and LDL uptake.

“Notably, knockdown of the latter led to an increase of over 50 % in LDLR mRNA levels, and a concomitant 40 % increase in LDLR protein abundance and LDL uptake.”

• cites [29] Li, 2009, Identification of mRNA binding proteins that regulate the stability of LDL receptor mRNA through AU-rich elements, J. Lipid Res. sourcePartly supported

  The Results report that depletion of hnRNP D, hnRNP I, and KSRP increased LDLR mRNA by more than 50% and increased LDLR protein expression. They report LDL uptake increases of 35%, 50%, and 41%, respectively, but do not give a 40% figure for protein abundance. Thus the claimed magnitude is supported approximately for KSRP-related uptake, not for protein abundance. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

SUMOylation of IDOL stabilizes the protein and enhances its ability to promote LDLR degradation.

“SUMOylation of IDOL stabilizes the protein and enhances its ability to promote LDLR degradation.”

• cites [70] Wang, 2021, SUMOylation of the ubiquitin ligase IDOL decreases LDL receptor levels and is reversed by SENP1, J. Biol. Chem. sourceSupported

It may state two separate claims as one.

RBM25 variants result in increased retention of intron 3 and are associated with elevated plasma LDL-cholesterol levels and potentially linked to unexplained familial hypercholesterolemia.

“Additionally, this study identified variants in RBM25, a U2-spliceosome component that resulted in increased retention of intron 3. Consequently, these variants were associated with elevated plasma LDL-cholesterol levels and were potentially linked to cases of unexplained familial hypercholesterolemia (FH).”

• cites [18] Zanoni, 2022, Posttranscriptional regulation of the human LDL receptor by the U2-spliceosome, Circ. Res. sourcePartly supported

  The section on RBM25 variants (page not specified) reports that rare variants were enriched in patients with familial hypercholesterolemia unexplained by known FH genes. But it found no significant increase in LDLR intron 3 retention when those mutants were expressed, and the Discussion says their effect on LDL uptake may be unrelated to intron 3 retention. The paper also reports that the RBM25 SNPs associated with LDL-cholesterol in the UK Biobank were associated with lower, not elevated, levels. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

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

IDOL consists of an N-terminal FERM domain and a C-terminal RING domain.

“IDOL consists of an N-terminal Ezrin/Radixin/Moesin homology (FERM) domain and a C-terminal RING domain [67].”

• cites [67] Martinelli, 2020, Structural analysis of the LDL receptor-interacting FERM domain in the E3 ubiquitin ligase IDOL reveals an obscured substrate-binding site, J. Biol. Chem. sourceSupported

It may state two separate claims as one.

The RING domain of IDOL possesses E3 ligase activity, stimulating poly-K63 and poly-K48 ubiquitination of the cytoplasmic tail of LDLR, thereby marking it for lysosomal degradation.

“The RING domain possesses E3 ligase activity, stimulating poly-K63 and poly-K48 ubiquitination of the cytoplasmic tail of LDLR, thereby marking it for lysosomal degradation [65,68].”

• cites [65] Sorrentino, 2011, Distinct functional domains contribute to degradation of the low density lipoprotein receptor (LDLR) by the E3 ubiquitin ligase inducible Degrader of the LDLR (IDOL), J. Biol. Chem. sourcePartly supported

  The Results (page unavailable) show that the IDOL RING domain promotes polyubiquitin-chain formation and that IDOL promotes Lys-63-linked ubiquitination of LDLR. The Discussion (page unavailable) proposes that this modification directs LDLR toward lysosomal degradation. Our copy does not establish Lys-48-linked ubiquitination of LDLR or locate the modification specifically on its cytoplasmic tail. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [68] Zhang, 2013, Both K63 and K48 ubiquitin linkages signal lysosomal degradation of the LDL receptor, J. Lipid Res. sourcePartly supported

  The Abstract reports that IDOL transfers ubiquitin chains to LDLR and that either K48 or K63 linkages can target LDLR to the lysosome. The Results identify IDOL’s RING domain as catalytic. The Discussion describes ubiquitination of residues in LDLR’s cytoplasmic tail as a possibility, rather than establishing that the measured K48- and K63-linked chains are attached there. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

miR-185 suppresses LDLR expression directly, but also indirectly by inhibiting SREBP-2-dependent gene expression.

“Similarly, miR-185 suppresses LDLR expression directly, but also indirectly by inhibiting SREBP-2-dependent gene expression [49].”

• cites [49] Yang, 2014, Identification of miR-185 as a regulator of de novo cholesterol biosynthesis and low density lipoprotein uptake, J. Lipid Res. sourcePartly supported

  The Results (page unavailable) show that miR-185 overexpression lowers LDLR expression and abolishes stimulated LDLR expression; the authors attribute this to repression of SREBP-2-dependent gene expression. The paper demonstrates direct targeting of SREBP-2 mRNA, not direct targeting of LDLR, so the claim of direct LDLR suppression is unsupported. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

SENP1 deSUMOylates IDOL, promotes its degradation, and thereby increases LDLR abundance and LDL uptake.

“Moreover, similar to removal of ubiquitin from IDOL by USP2, the SUMO-specific peptidase 1 (SENP1) deSUMOylates IDOL, promotes its degradation, and thereby increases LDLR abundance and LDL uptake [70].”

• cites [70] Wang, 2021, SUMOylation of the ubiquitin ligase IDOL decreases LDL receptor levels and is reversed by SENP1, J. Biol. Chem. sourceSupported

It may state two separate claims as one.

Silencing hepatic IDOL expression in non-human primates did not decrease circulating LDL levels significantly, but blunted the high fat diet-induced increase in plasma LDL upon pharmacological LXR activation.

“Silencing hepatic IDOL expression did not decrease circulating LDL levels significantly.However, this treatment effectively blunted the high fat diet-induced increase in plasma LDL upon pharmacological LXR activation.”

• cites [78] Hong, 2014, The LXR-Idol axis differentially regulates plasma LDL levels in primates and mice, Cell Metabol. sourceSupported

It may state two separate claims as one.

Among the identified RBPs, AUH, CPSF1, and GRSF1 act as stabilizing factors, while hnRNP D, hnRNP I, and KSRP are destabilizing factors.

“Among these, AUH, CPSF1, and GRSF1 were found to act as stabilizing factors, while hnRNP D, hnRNP I, and KSRP are destabilizing factors [29].”

• cites [29] Li, 2009, Identification of mRNA binding proteins that regulate the stability of LDL receptor mRNA through AU-rich elements, J. Lipid Res. sourcePartly supported

  The Results report that depleting AUH, CPSF1, or GRSF1 reduced LDLR mRNA expression, consistent with a protective role, but the paper does not establish that these three directly stabilize the mRNA. It explicitly identifies hnRNP D, hnRNP I, and KSRP as negative regulators of LDLR mRNA stability (Abstract; Results). (LLM, conf=0.88)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

IDOL robustly promotes its own ubiquitination, making it a short-lived protein with a half-life of about 5 minutes.

“Additionally, IDOL robustly promotes its own ubiquitination [62,66,67], making it a short-lived protein (t 1/2 -5 min [69]).”

• cites [62] Zelcer, 2009, LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor, Science sourcePartly supported

  In the passage labeled Abstract (Fig. S4A), the paper reports low IDOL protein levels and increased levels after RING-domain mutation, suggesting instability and raising the possibility that IDOL catalyzes its own degradation. It does not demonstrate robust self-ubiquitination. The approximately five-minute half-life is attributed to a separate citation [69] in the citing sentence and is not reported in this paper. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [66] Calkin, 2011, FERM-dependent E3 ligase recognition is a conserved mechanism for targeted degradation of lipoprotein receptors, Proc. Natl. Acad. Sci. U.S.A. sourceNot checked — no full text of the source
• cites [67] Martinelli, 2020, Structural analysis of the LDL receptor-interacting FERM domain in the E3 ubiquitin ligase IDOL reveals an obscured substrate-binding site, J. Biol. Chem. sourceNot checked yet

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

• cites [69] Nelson, 2016, The deubiquitylase USP2 regulates the LDLR pathway by counteracting the E3-ubiquitin ligase IDOL, Circ. Res. sourcePartly supported

  In “USP2 Deubiquitylates and Stabilizes IDOL” (page unavailable), the paper describes IDOL as highly unstable, likely because of its high autoubiquitylation activity, and reports that USP2 extends its half-life. It does not give a half-life of about 5 minutes, which is the specific point attached to this source’s citation [69]. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

Different research groups have identified more than ten different compounds that enhance LDLR mRNA stability and subsequently increase LDLR protein levels, although the mechanisms and specificity are not fully understood.

“Adding to the complexity of LDLR mRNA regulation, different research groups have identified more than ten different compounds that enhance LDLR mRNA stability and subsequently increase LDLR protein levels, although the mechanism(s) behind these effects and how specific they are is not yet fully understood [19,21,24,32,[35][36][37][38][39][40][41].”

• cites [19] Bjune, 2018, Triciribine increases LDLR expression and LDL uptake through stabilization of LDLR mRNA, Sci. Rep. sourceSupported
• cites [21] Bjune, 2019, Inhibitors of AKT kinase increase LDL receptor mRNA expression by two different mechanisms, PLoS One sourceSupported
• cites [24] Mnasri, 2018, 5-Azacytidine engages an IRE1alpha-EGFR-ERK1/2 signaling pathway that stabilizes the LDL receptor mRNA, Biochim. Biophys. Acta Gene. Regul. Mech. sourceNot checked — no full text of the source
• cites [32] Kong, 2004, Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins, Nat. Med. sourceNot checked — no full text of the source

It may state two separate claims as one.

Transient or transgenic hepatic expression of Idol dramatically decreases the level of LDLR in the liver and results in a plasma lipid profile that phenocopies that of LDLR-KO mice.

“Transient or transgenic hepatic expression of Idol dramatically decreases the level of LDLR in the liver and results in a plasma lipid profile that phenocopies that of LDLR-KO mice [62,71,72].”

• cites [62] Zelcer, 2009, LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor, Science sourcePartly supported

  The indexed passage labeled Abstract (page unavailable) reports that adenoviral expression of Idol in mouse liver markedly reduced LDLR protein and produced a plasma lipoprotein profile reminiscent of Ldlr-knockout mice. It does not report transgenic hepatic expression, so that part of the sentence is not supported by this source. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [71] Somanathan, 2014, AAV vectors expressing LDLR gain-of-function variants demonstrate increased efficacy in mouse models of familial hypercholesterolemia, Circ. Res. sourcePartly supported

  In Results (section “hLDLR-K809R/C818A escapes hIDOL regulation”; page unavailable), liver-directed AAV expression of human IDOL in LDLR-heterozygous mice increased non-HDL cholesterol and caused loss of endogenous mouse LDLR. The paper does not report transgenic hepatic IDOL expression or establish that the resulting plasma lipid profile phenocopies LDLR-knockout mice. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [72] Calkin, 2014, Transgenic expression of dominant-active IDOL in liver causes diet-induced hypercholesterolemia and atherosclerosis in mice, Circ. Res. sourcePartly supported

  The Results (Generation of L-sIDOL transgenic mice; page unavailable) report markedly reduced hepatic LDLR after transgenic expression. The plasma-lipid Results report increased LDL cholesterol and some similarities to LDLR-KO mice, but cholesterol and triglyceride elevations did not reach KO levels. This paper studies chronic transgenic expression, not transient hepatic expression. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

IDOL and GOLIATH are spatially separated within the cell, with IDOL localized to the plasma membrane and GOLIATH to the endosomal system.

“It is noteworthy that IDOL and GOLIATH are spatially separated within the cell, with IDOL localized to the plasma membrane and GOLIATH to the endosomal system [65,81].”

• cites [65] Sorrentino, 2011, Distinct functional domains contribute to degradation of the low density lipoprotein receptor (LDLR) by the E3 ubiquitin ligase inducible Degrader of the LDLR (IDOL), J. Biol. Chem. sourcePartly supported

  The Results and Discussion (page not specified) place the IDOL FERM domain at or near the plasma membrane when co-expressed with LDLR in HepG2 cells. This is conditional evidence about an IDOL domain, not a general localization finding for full-length IDOL. Our copy does not address GOLIATH or establish that the two proteins are spatially separated. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [81] Yamazaki, 2013, Goliath family E3 ligases regulate the recycling endosome pathway via VAMP3 ubiquitylation, EMBO J. sourceNot checked — no full text of the source

It may state two separate claims as one.

ASGR1 binds to glycoproteins containing galactose or N-acetylgalactosamine, while ASGR2 mediates the internalization and trafficking of the glycoprotein to lysosomes for degradation.

“ASGR1 binds to glycoproteins containing galactose (Gal) or N-acetylgalactosamine (GalNAc), while ASGR2 mediates the internalization and trafficking of the glycoprotein to the lysosomes for degradation [83].”

• cites [83] Hoober, 2020, ASGR1 and its enigmatic relative, CLEC10A, Int. J. Mol. Sci. sourcePartly supported

  Section 2 (ASGR1; page not provided) describes ASGR1’s preference for GalNAc over Gal and says that bound glycoprotein ligands are internalized and degraded in lysosomes. It describes this process for the receptor generally, not as a distinct role mediated by ASGR2. The claimed division of labor between ASGR1 and ASGR2 is therefore not supported. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

siRNA-mediated silencing or ablation of BMP1 in HepG2 and CHO cells increased the levels of full-length LDLR and dramatically decreased the appearance of the truncated LDLR.

“Second, siRNA-mediated silencing or ablation of BPM1 in HepG2 and CHO cells increased the levels of full-length LDLR and dramatically decreased the appearance of the truncated LDLR [56,57].”

• cites [56] Banerjee, 2019, Proteolysis of the low density lipoprotein receptor by bone morphogenetic protein-1 regulates cellular cholesterol uptake, Sci. Rep. sourcePartly supported

  The Results section (Fig. 3; page unavailable) reports that BMP1 siRNA knockdown in HepG2 cells almost completely abolished production of the truncated LDLR fragments. Its rescue experiment also links BMP1 activity to a decrease in full-length LDLR. The Methods section describes CHO-A7 cells transfected with LDLR constructs, not BMP1 silencing or ablation in those cells; the claim’s CHO-cell and ablation portions are unsupported. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [57] Strom, 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. sourceNot checked — no full text of the source

It may state two separate claims as one.

Liver-specific ablation of Mt1-mmp increased the level of hepatic LDLR, decreased appearance of sLDLR in plasma, and attenuated atherosclerotic plaque formation.

“Accordingly, liver-specific ablation of Mt1-mmp increased the level of hepatic LDLR, decreased appearance of sLDLR in plasma, attenuated atherosclerotic plaque formation [99].”

• cites [99] Alabi, 2021, Membrane type 1 matrix metalloproteinase promotes LDL receptor shedding and accelerates the development of atherosclerosis, Nat. Commun. sourcePartly supported

  The Results section (“MT1-MMP promotes LDLR cleavage in vivo”; page unavailable) reports that liver-specific MT1-MMP knockout increased hepatic LDLR and reduced plasma sLDLR. But the Results section on atherosclerosis reports no significant reduction in aortic-sinus lesion size after hepatic MT1-MMP knockdown in apoE−/− mice; it found reduced aortic cholesteryl ester accumulation instead. Thus, the claimed attenuation of plaque formation is not supported. (LLM, conf=0.91)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

ASGR1 deficiency led to inhibition of HMG-CoA reductase, ultimately resulting in decreased de novo cholesterol synthesis and VLDL secretion.

“ASGR1 deficiency led to the inhibition of HMG-CoA reductase (HMGCR), ultimately resulting in decreased de novo cholesterol synthesis and VLDL secretion.”

• cites [85] Xie, 2021, Deficiency of ASGR1 in pigs recapitulates reduced risk factor for cardiovascular disease in humans, PLoS Genet. sourceSupported

It may state two separate claims as one.

Using antisense oligonucleotides to reduce Goliath expression in vivo led to effective hepatic silencing (~90%), a significant increase in hepatic LDLR protein levels, and a marked decrease in total plasma LDL and HDL cholesterol levels.

“Using antisense oligonucleotides (ASOs) to reduce Goliath expression in vivo led to effective hepatic silencing (~90 %), and this resulted in a significant increase in hepatic LDLR protein levels and a marked decrease in total plasma LDL and HDL cholesterol levels.”

• cites [80] Clifford, 2023, RNF130 regulates LDLR availability and plasma LDL cholesterol levels, Circ. Res. sourceSupported

It may state two separate claims as one.

In mice, treatment with GSIs reduced plasma triglycerides, VLDL-TG, and non-HDL cholesterol.

“Specifically, mice treated with GSIs showed reduced plasma triglycerides, VLDL-TG, and non-HDL cholesterol.”

• cites [114] Kim, 2018, Gamma-secretase inhibition lowers plasma triglyceride-rich lipoproteins by stabilizing the LDL receptor, Cell Metabol. sourceSupported

It may state two separate claims as one.

Mice with either global or liver-specific ablation of Goliath showed moderately increased hepatic LDLR levels and lower plasma cholesterol levels, primarily in fractions associated with LDL.

“This study went further and demonstrated that mice with either global or liver-specific ablation of Goliath showed moderately increased hepatic LDLR levels and lower plasma cholesterol levels, primarily in fractions associated with LDL [80].”

• cites [80] Clifford, 2023, RNF130 regulates LDLR availability and plasma LDL cholesterol levels, Circ. Res. sourcePartly supported

  The Results sections on partial knockout and liver-specific disruption report increased hepatic LDLR and reduced plasma cholesterol, mainly in the LDL fraction. However, the surviving whole-body knockout mice retained about 30% Rnf130 mRNA expression in the liver, and the liver-targeted experiment reports reduced expression rather than complete ablation. Thus, “ablation” overstates both interventions. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

The shed sLDLR retains its ability to bind LDL, effectively competing with the LDLR for clearance of the particle.

“Intriguingly, the shed sLDLR retains its ability to bind LDL, effectively competing with the LDLR for clearance of the particle.”

• cites [99] Alabi, 2021, Membrane type 1 matrix metalloproteinase promotes LDL receptor shedding and accelerates the development of atherosclerosis, Nat. Commun. sourcePartly supported

  The Results section (‘sLDLR and plasma lipoproteins’; page not provided) reports that sLDLR associates with LDL and other apoB- and apoE-containing lipoproteins, supporting its ability to bind LDL. The Discussion (page not provided) treats whether sLDLR-bound LDL is taken up as efficiently by cell-surface LDLR as an open question; it does not establish that sLDLR competes with LDLR for LDL clearance. (LLM, conf=0.89)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

Specific inhibition of hepatic γ-secretase counters diet-induced hepatic steatosis, dyslipidemia, and atherosclerosis in mice.

“Furthermore, specific inhibition of hepatic γ-secretase counters diet-induced hepatic steatosis, dyslipidemia, and atherosclerosis in mice [115].”

• cites [115] Kim, 2020, Liver-selective gamma-secretase inhibition ameliorates diet-induced hepatic steatosis, dyslipidemia and atherosclerosis, Biochem. Biophys. Res. Commun. sourceSupported

It may state two separate claims as one.

In mice, liver-specific overexpression of Goliath moderately decreased hepatic LDLR abundance without changing its mRNA levels, and this change was accompanied by increased plasma LDL.

“In mice, liver-specific overexpression of Goliath moderately decreased hepatic LDLR abundance without changing its mRNA levels, and this change was accompanied by increased plasma LDL [80].”

• cites [80] Clifford, 2023, RNF130 regulates LDLR availability and plasma LDL cholesterol levels, Circ. Res. sourceSupported

It may state two separate claims as one.

The LDLR is cleaved in the linker region between LA repeat 4 and 5, with Asp193 being crucial for this cleavage.

“Multiple studies have shown that the LDLR is cleaved in the linker region between LA repeat 4 and 5 [107], with Asp193 being crucial for this cleavage [56,106].”

• cites [107] Tveten, 2012, Characterization of a naturally occurring degradation product of the LDL receptor, Mol. Genet. Metabol. sourceNot checked — no full text of the source
• cites [56] Banerjee, 2019, Proteolysis of the low density lipoprotein receptor by bone morphogenetic protein-1 regulates cellular cholesterol uptake, Sci. Rep. sourceSupported
• cites [106] Strom, 2019, Strategies to prevent cleavage of the linker region between ligand-binding repeats 4 and 5 of the LDL receptor, Hum. Mol. Genet. sourceNot checked — no full text of the source

It may state two separate claims as one.

ASGR1 binds the glycosylated ectodomain of LDLR, resulting in internalization and ultimately degradation in the lysosomes.

“ASGR1 binds the glycosylated ectodomain of LDLR resulting in internalization and ultimately degradation in the lysosomes.”

• cites [84] Susan-Resiga, 2021, Asialoglycoprotein receptor 1 is a novel PCSK9-independent ligand of liver LDLR cleaved by furin, J. Biol. Chem. sourcePartly supported

  The Results section (Fig. 8C) reports that ASGR1 binds both mature N- and O-glycosylated LDLR and immature LDLR, and the Discussion (Fig. 9) says ASGR1 promotes LDLR degradation. Our copy does not establish binding specifically to the LDLR ectodomain or show that ASGR1 causes LDLR internalization followed by lysosomal degradation. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

CSDE1, hnRNPD, hnRNPI, KSRP, ZFP36L1, and ZFP36L2 bind to AREs in the 3′UTR and lead to degradation of LDLR mRNA, decreasing LDLR.

“CSDE1, hnRNPD, hnRNPI, KSRP, ZFP36L1, ZFP36L2 Bind to AREs in the 3′UTR and lead to degradation of LDLR mRNA ↓ [29-31]”

• cites [29] Li, 2009, Identification of mRNA binding proteins that regulate the stability of LDL receptor mRNA through AU-rich elements, J. Lipid Res. sourcePartly supported

  The Abstract (page not provided) states that hnRNP D, hnRNP I, and KSRP bind AREs in the LDLR 3′UTR and that silencing them increases LDLR mRNA and protein levels, supporting their role in promoting decay. The passages do not establish the same binding and decay-promoting role for CSDE1, ZFP36L1, or ZFP36L2. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [30] Adachi, 2014, ZFP36L1 and ZFP36L2 control LDLR mRNA stability via the ERK-RSK pathway, Nucleic Acids Res. sourcePartly supported

  The Results and Discussion (pages not provided) show that ZFP36L1 and ZFP36L2 bind the LDLR 3′-UTR ARE1 region, destabilize LDLR mRNA, and reduce LDLR protein levels. The Discussion reports KHSRP, hnRNPD and PTBP1 as LDLR-destabilizing proteins, but does not establish that each binds an LDLR ARE. Our copy does not identify CSDE1 as an LDLR-binding or destabilizing protein. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [31] Smith, 2022, Cold shock domain-containing protein E1 is a posttranscriptional regulator of the LDL receptor, Sci. Transl. Med. sourcePartly supported

  The Results section reports that CSDE1 promotes LDLR mRNA decay through its 3′UTR and that an ARE is required for its full effect. The Discussion says CSDE1 was found to bind LDLR 3′UTR transcripts, but the paper does not establish that it binds the ARE itself or substantiate the same mechanism for all six listed proteins. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

GOLIATH (RNF130) promotes LDLR internalization and lysosomal degradation, decreasing LDLR.

“GOLIATH (RNF130) Promotes LDLR internalization and lysosomal degradation ↓ [80]”

• cites [80] Clifford, 2023, RNF130 regulates LDLR availability and plasma LDL cholesterol levels, Circ. Res. sourcePartly supported

  The Results section reports that RNF130 reduces cell-surface and total LDLR and redistributes LDLR to intracellular vesicles. Those vesicles co-localize with a late-endosome and lysosome marker, which the authors describe as consistent with lysosomal degradation; they do not establish RNF130-driven lysosomal degradation as definitively as the claim states. No page number is available in our copy. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

IDOL promotes LDLR ubiquitylation and lysosomal degradation, decreasing LDLR.

“IDOL (Inducible degrader of LDLR) Promotes LDLR ubiquitylation and lysosomal degradation ↓ [62]”

• cites [62] Zelcer, 2009, LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor, Science sourceSupported

It may state two separate claims as one.

miR-27a, miR-27b, miR-128-1, miR-128-3p, miR-130b, miR-148a, miR-184a, miR-185, and miR-301b inhibit expression of the LDLR, decreasing LDLR.

“miR-27a, miR-27b, miR-128-1, miR-128-3p, miR-130b, miR-148a, miR-184a, miR-185, miR-301b Inhibit expression of the LDLR ↓ [43-48]”

• cites [43] Alvarez, 2015, MicroRNA-27a decreases the level and efficiency of the LDL receptor and contributes to the dysregulation of cholesterol homeostasis, Atherosclerosis sourcePartly supported

  The Results section shows that miR-27a decreases LDLR mRNA and protein in HepG2 cells. The cited paper does not establish the same LDLR effect for the other listed miRNAs; its Discussion says prior findings suggest miR-27a, but not miR-27b, modulates LDLR in differentiated hepatocyte-like cells. The citation therefore supports the miR-27a part of the grouped claim, not the full list. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [44] Goedeke, 2015, MicroRNA-148a regulates LDL receptor and ABCA1 expression to control circulating lipoprotein levels, Nat. Med. sourceSupported
• cites [45] Goedeke, 2015, miR-27b inhibits LDLR and ABCA1 expression but does not influence plasma and hepatic lipid levels in mice, Atherosclerosis sourceSupported
• cites [46] Wagschal, 2015, Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis, Nat. Med. sourcePartly supported

  The Results section on microRNA regulation of lipid-related genes reports that miR-128-1, miR-130b, miR-148a, and miR-301b decreased LDLR levels in HepG2 cells. It does not establish the claimed LDLR inhibition for the other five listed miRNAs: miR-27a, miR-27b, miR-128-3p, miR-184a, and miR-185. Page numbers are unavailable in our copy. (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites [47] Jiang, 2015, microRNA-185 modulates low density lipoprotein receptor expression as a key posttranscriptional regulator, Atherosclerosis sourceNot checked — no full text of the source
• cites [48] Chandra, 2021, Inhibition of microRNA-128-3p attenuates hypercholesterolemia in mouse model, Life Sci. sourceNot checked — no full text of the source

It may state two separate claims as one.

ASGR1 promotes LDLR internalization and degradation, decreasing LDLR.

“ASGR1 (Asialoglycoprotein receptor 1) Promotes LDLR internalization and degradation; Regulates SREBP2dependent signaling and expression of PCSK9 ↓ [84,85]”

• cites [84] Susan-Resiga, 2021, Asialoglycoprotein receptor 1 is a novel PCSK9-independent ligand of liver LDLR cleaved by furin, J. Biol. Chem. sourcePartly supported

  The Results section on ASGR1 binding and LDLR degradation (Fig. 9; page unavailable) reports that ASGR1 reduces cell-surface and total LDLR levels, while silencing ASGR1 increases total LDLR. The paper measures internalization of LDL, but the passages do not establish that ASGR1 promotes internalization of LDLR itself. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [85] Xie, 2021, Deficiency of ASGR1 in pigs recapitulates reduced risk factor for cardiovascular disease in humans, PLoS Genet. sourceSupported

It may state two separate claims as one.

MT1-MMP promotes ectodomain shedding of LDLR, decreasing LDLR.

“MT1-MMP (Membrane type-I matrix metalloproteinase) Promotes ectodomain shedding of LDLR ↓ [99]”

• cites [99] Alabi, 2021, Membrane type 1 matrix metalloproteinase promotes LDL receptor shedding and accelerates the development of atherosclerosis, Nat. Commun. sourceSupported

It may state two separate claims as one.

SUMO1 enhances IDOL-mediated degradation of the LDLR, decreasing LDLR.

“Small Ubiquitin-like Modifier 1 (SUMO1) Enhances IDOL-mediated degradation of the LDLR ↓ [70]”

• cites [70] Wang, 2021, SUMOylation of the ubiquitin ligase IDOL decreases LDL receptor levels and is reversed by SENP1, J. Biol. Chem. sourceSupported

It may state two separate claims as one.

miR-224 and miR-520d inhibit expression of IDOL, increasing LDLR.

“miR224, miR520d Inhibit expression of IDOL ↑ [50-55]”

• cites [50] Salerno, 2020, LDL receptor pathway regulation by miR-224 and miR-520d, Front Cardiovasc. Med. sourceSupported
• cites [51] Naeli, 2017, Post-transcriptional Regulation of PCSK9 by miR-191, miR-222, and miR-224, Front. Genet. sourcePartly supported

  The Discussion (page not provided) reports that miR-224 directly targets and reduces PCSK9, which promotes LDLR degradation. This supports a link between miR-224 and LDLR regulation, but the paper does not say that miR-224 inhibits IDOL or that miR-520d has either effect. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [52] Bai, 2017, A retrospective study of NENs and miR-224 promotes apoptosis of BON-1 cells by targeting PCSK9 inhibition, Oncotarget sourcePartly supported

  The Results section (page unavailable) shows that miR-224 reduces PCSK9 expression in BON-1 cells, and the Discussion identifies PCSK9 as a regulator of the LDL receptor. Our copy does not show that miR-224 inhibits IDOL, address miR-520d, or demonstrate an increase in LDLR. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites [53] Dong, 2020, microRNA-483 ameliorates hypercholesterolemia by inhibiting PCSK9 production, JCI Insight sourceCould not verify

  The Results section reports that miR-224 reduced activity of a PCSK9 3′-UTR reporter, but does not say it inhibits IDOL. The Introduction and Discussion attribute increased LDLR expression to miR-483 targeting PCSK9. Searches for IDOL and miR-520d found no passage addressing the claimed mechanism. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [54] van Solingen, 2021, High-throughput screening identifies MicroRNAs regulating human PCSK9 and hepatic low-density lipoprotein receptor expression, Front Cardiovasc. Med. sourcePartly supported

  The Results section reports that miR-224 reduced IDOL mRNA and increased LDLR protein in HepG2 cells. It does not report IDOL inhibition or increased LDLR for miR-520d; the Introduction mentions miR-520d only as a potential inhibitor of PCSK9. (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites [55] Beehler, 2021, A common polymorphism in the FADS1 locus links miR1908 to low-density lipoprotein cholesterol through BMP1, Arterioscler. Thromb. Vasc. Biol. sourceCould not verify

  The ‘Identification of Potential Target Genes of miR-1908-5p’ section discusses miR-1908-5p and LDLR cleavage, not miR-224 or miR-520d. Searches for those miRNAs and for IDOL found no passage in our copy addressing whether they inhibit IDOL or increase LDLR. (LLM, conf=0.75)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

ASGR1 regulates SREBP2-dependent signaling and expression of PCSK9, decreasing LDLR.

“ASGR1 (Asialoglycoprotein receptor 1) Promotes LDLR internalization and degradation; Regulates SREBP2dependent signaling and expression of PCSK9 ↓ [84,85]”

• cites [84] Susan-Resiga, 2021, Asialoglycoprotein receptor 1 is a novel PCSK9-independent ligand of liver LDLR cleaved by furin, J. Biol. Chem. sourcePartly supported

  The Results section reports that ASGR1 reduces LDLR protein levels and enhances its degradation, supporting that part of the claim. But the Results and Discussion say ASGR1 knockdown did not change SREBP2 mRNA or PCSK9 expression, and that its effect on LDLR is independent of PCSK9. The claimed regulation of SREBP2-dependent signaling and PCSK9 expression is therefore not supported. (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites [85] Xie, 2021, Deficiency of ASGR1 in pigs recapitulates reduced risk factor for cardiovascular disease in humans, PLoS Genet. sourcePartly supported

  The Discussion (page unavailable) reports that ASGR1 deficiency increases hepatic LDLR protein and cites evidence that ASGR1 binds and degrades LDLR. It does not establish SREBP2-dependent signaling; instead, it excludes a PCSK9-mediated explanation for the LDLR change because plasma PCSK9 levels were comparable in ASGR1-deficient and control pigs. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

USP2 counters IDOL-mediated degradation of the LDLR, increasing LDLR.

“USP2 (Ubiquitin-specific protease 2) Counters IDOL-mediated degradation of the LDLR ↑ [69]”

• cites [69] Nelson, 2016, The deubiquitylase USP2 regulates the LDLR pathway by counteracting the E3-ubiquitin ligase IDOL, Circ. Res. sourceSupported

The quote only partly states this claim.

AMG-529 treatment did not show a dose-related effect on lipid metabolism.

“However, AMG-59 treatment did not show a dose related effect on lipid metabolism [119], and its development has been halted to the best of our knowledge.”

• cites [119] Janiszewski, 2019, A randomized, placebo-controlled, double-blind, ascending single-dose, phase 1 study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of amg 529, a novel ANTI-ASGR1 monoclonal antibody, in healthy subjects, J. Am. Coll. Cardiol. sourceSupported

It may state two separate claims as one.

AUH, CPSF1, and GRSF1 bind to AREs in the 3′UTR and stabilize LDLR mRNA, increasing LDLR.

“AUH, CPSF1, GRSF1 Bind to AREs in the 3′UTR and stabilize LDLR mRNA ↑ [29]”

• cites [29] Li, 2009, Identification of mRNA binding proteins that regulate the stability of LDL receptor mRNA through AU-rich elements, J. Lipid Res. sourcePartly supported

  The Results (page unavailable) report that depleting AUH, CPSF1, or GRSF1 reduced LDLR mRNA levels by 36–44%, supporting a role in maintaining its expression. But the paper does not establish that these three proteins bind the AREs or directly stabilize LDLR mRNA; its ARE-binding experiments identify hnRNP D, hnRNP I, and KSRP instead. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

UCAU motifs are recognized as critical regulatory elements and act as potential binding sites for specific RNA binding proteins such as Nova-1.

“These UCAU motifs are recognized as critical regulatory elements and act as potential binding sites for specific RNA binding protein such as the Nova-1 KH-type RNA-binding protein [33,34].”

• cites [33] Buckanovich, 1997, The neuronal RNA binding protein Nova-1 recognizes specific RNA targets in vitro and in vivo, Mol. Cell Biol. sourceNot checked — no full text of the source
• cites [34] Jensen, 2000, The tetranucleotide UCAY directs the specific recognition of RNA by the Nova K-homology 3 domain, Proc. Natl. Acad. Sci. U.S.A. sourceNot checked yet

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

It may state two separate claims as one.

Absence of Idol in hamsters did not alter hepatic LDLR abundance or plasma cholesterol levels, but resulted in significantly reduced plasma triglycerides and protection from development of atherosclerosis.

“Absence of Idol in hamsters did not alter hepatic LDLR abundance or plasma cholesterol levels.However, this resulted in significantly reduced plasma triglycerides and protection from development of atherosclerosis [77].”

• cites [77] Liang, 2022, Idol depletion protects against spontaneous atherosclerosis in a hamster model of familial hypercholesterolemia, Oxid. Med. Cell. Longev. sourceNot checked yet

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

It may state two separate claims as one.

Inhibition of miR-128-3p increases hepatic LDLR abundance and reduces plasma LDL-cholesterol in mice.

“as was the case with inhibition of miR-128-3p [48].”

• cites [48] Chandra, 2021, Inhibition of microRNA-128-3p attenuates hypercholesterolemia in mouse model, Life Sci. sourceNot checked — no full text of the source

It may state two separate claims as one.

Inhibition of miR-185 in APOE-knockout mice increases LDLR abundance, reduces plasma cholesterol, and attenuates atherosclerotic plaque formation.

“Similarly, inhibition of miR-185 in APOE-knockout mice increases LDLR abundance, reduces plasma cholesterol, and attenuates atherosclerotic plaque formation [47]”

• cites [47] Jiang, 2015, microRNA-185 modulates low density lipoprotein receptor expression as a key posttranscriptional regulator, Atherosclerosis sourceNot checked — no full text of the source

It may state two separate claims as one.

A whole-genome CRISPR-Cas9 screen identified CSDE1 as an RBP that enhances LDLR mRNA decay, confirmed in HepG2 cells, zebrafish, and mice.

“More recently, the application of a whole-genome CRISPR-Cas9 screen further identified CSDE1 as another RBP that enhances LDLR mRNA decay, an effect confirmed in various models including HepG2 cells, zebrafish, and mice [31].”

• cites [31] Smith, 2022, Cold shock domain-containing protein E1 is a posttranscriptional regulator of the LDL receptor, Sci. Transl. Med. sourceNot checked yet

It may state two separate claims as one.

miR-27a directly suppresses LDLR and significantly increases PCSK9 expression, which synergistically leads to reduced LDLR.

“Notably, miR-27a not only directly suppresses LDLR but also significantly increases PCSK9 expression, which synergistically leads to reduced LDLR [43].”

• cites [43] Alvarez, 2015, MicroRNA-27a decreases the level and efficiency of the LDL receptor and contributes to the dysregulation of cholesterol homeostasis, Atherosclerosis sourceNot checked yet

It may state two separate claims as one.

Anti-sense oligonucleotide-mediated inhibition of miR-148a increases hepatic LDLR abundance and reduces plasma LDL-cholesterol in mice.

“For example, anti-sense oligonucleotide-mediated inhibition of miR-148a increases hepatic LDLR abundance and reduces plasma LDL-cholesterol in mice [44]”

• cites [44] Goedeke, 2015, MicroRNA-148a regulates LDL receptor and ABCA1 expression to control circulating lipoprotein levels, Nat. Med. sourceNot checked yet

It may state two separate claims as one.

Retention of intron 3 results in a prematurely truncated LDLR protein that lacks the transmembrane domain and is unable to mediate LDL endocytosis.

“This retention results in a prematurely truncated LDLR protein that lacks the transmembrane domain and is thus unable to mediate LDL endocytosis [18].”

• cites [18] Zanoni, 2022, Posttranscriptional regulation of the human LDL receptor by the U2-spliceosome, Circ. Res. sourceNot checked yet

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

AREs play a crucial role in regulating mRNA stability and are present in 22% of all human 3′UTRs, establishing them as the most common regulatory motifs for mRNA stability.

“These AREs play a crucial role in regulating mRNA stability and are present in 22 % of all human 3′UTRs, establishing them as the most common regulatory motifs for mRNA stability [26].”

• cites [26] Bakheet, 2018, ARED-Plus: an updated and expanded database of AU-rich element-containing mRNAs and pre-mRNAs, Nucleic Acids Res. sourceNot checked yet

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

It may state two separate claims as one.

Inhibition of miR-27a results in a ~1.5-fold increase in LDLR mRNA and protein levels and a ~50% decrease in PCSK9 in HepG2 cells.

“Accordingly, inhibition of miR-27a results in a ~1.5-fold increase in LDLR mRNA and protein levels and a ~50 % decrease in PCSK9 in HepG2 cells.”

• cites [43] Alvarez, 2015, MicroRNA-27a decreases the level and efficiency of the LDL receptor and contributes to the dysregulation of cholesterol homeostasis, Atherosclerosis sourceNot checked yet

It may state two separate claims as one.

Carriers of the rs-174561-C variant in the miR-1908-5p locus have increased expression of miR-1908-5p and consequently lower circulating LDL.

“Carriers of the rs-174561-C variant in the miR-1908-5p locus have increased expression of miR-1908-5p and consequently lower circulating LDL [55].”

• cites [55] Beehler, 2021, A common polymorphism in the FADS1 locus links miR1908 to low-density lipoprotein cholesterol through BMP1, Arterioscler. Thromb. Vasc. Biol. sourceNot checked yet

It may state two separate claims as one.

Loss of Asgr1 in APOE-knockout mice protected them from Western diet-induced development of atherosclerosis, attributed to a combination of LXRα-mediated cholesterol efflux, decreased expression of Mttp and VLDL secretion, enhanced peripheral LPL activity, and increased hepatic LDLR abundance and LDL clearance.

“This study demonstrates that loss of Asgr1 in APOE-knockout mice were protected from Western diet-induced development of atherosclerosis.This was attributed to a combination of LXRα-mediated cholesterol efflux, decreased expression of Mttp and VLDL secretion, enhanced peripheral LPL activity, and increased hepatic LDLR abundance and LDL clearance.”

• cites [89] Zhang, 2024, ASGR1 deficiency inhibits atherosclerosis in western diet-fed ApoE(-/-) mice by regulating lipoprotein metabolism and promoting cholesterol efflux, Arterioscler. Thromb. Vasc. Biol. sourceNot checked yet

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

It may state two separate claims as one.

The BMP1 inhibitor UK383367 increases the amount of intracellular full-length LDLR while reducing the appearance of the LA 1-4 fragment in CHO cells.

“First, the BMP1 inhibitor UK383367 increases the amount of intracellular full-length LDLR while reducing the appearance of the LA 1-4 fragment in CHO cells [57].”

• cites [57] Strom, 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. sourceNot checked — no full text of the source

It may state two separate claims as one.

ASGR-stimulated degradation of the LDLR is countered by Furin-mediated cleavage of ASGR1, a process that inactivates it.

“ASGR-stimulated degradation of the LDLR is countered by Furin-mediated cleavage of ASGR1, a process that inactivates it [84].”

• cites [84] Susan-Resiga, 2021, Asialoglycoprotein receptor 1 is a novel PCSK9-independent ligand of liver LDLR cleaved by furin, J. Biol. Chem. sourceNot checked yet

It may state two separate claims as one.

While LDLR mRNA levels were lower in ASGR1-deficient pigs compared to WT controls, hepatic LDLR protein levels and LDL uptake were increased.

“Additionally, while LDLR mRNA levels were lower in ASGR1-deficient pigs (compared to WT controls), hepatic LDLR protein levels and LDL uptake were increased [85].”

• cites [85] Xie, 2021, Deficiency of ASGR1 in pigs recapitulates reduced risk factor for cardiovascular disease in humans, PLoS Genet. sourceNot checked yet

It may state two separate claims as one.

Absence of Presenilin in cultured embryonic mouse fibroblasts led to an increase in surface LDLR levels, but unexpectedly to a decrease in LDL uptake.

“Surprisingly, the absence of Presenilin led to an increase in surface LDLR levels, but unexpectedly to a decrease in LDL uptake.”

• cites [111] Tamboli, 2008, Loss of gamma-secretase function impairs endocytosis of lipoprotein particles and membrane cholesterol homeostasis, J. Neurosci. sourceNot checked yet

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

AMG-529 treatment appeared to be safe, well tolerated, and efficient in inhibiting ASGR1.

“The treatment appeared to be safe, well tolerated, and efficient in inhibiting ASGR1.”

• cites [119] Janiszewski, 2019, A randomized, placebo-controlled, double-blind, ascending single-dose, phase 1 study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of amg 529, a novel ANTI-ASGR1 monoclonal antibody, in healthy subjects, J. Am. Coll. Cardiol. sourceNot checked yet

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

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

A detailed understanding of the post-transcriptional mechanisms that regulate LDLR expression may inform new lipid-lowering therapeutic interventions.

“A detailed understanding of the post-transcriptional mechanisms that regulate LDLR expression may inform on new lipid-lowering therapeutic interventions.”

It may state two separate claims as one.

MT1-MMP is regulated by TNFα, and in HepG2 cells treated with TNFα, the release of sLDLR is increased.

“A study by Zegeye et al. found that MT1-MMP is regulated by TNFα [102].Accordingly, in HepG2 cells treated with TNFα, the release of sLDLR is increased.”

• cites [102] Zegeye, 2023, Soluble LDL-receptor is induced by TNF-alpha and inhibits hepatocytic clearance of LDL-cholesterol, J. Mol. Med. (Berl.) sourceNot checked yet

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

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

AMG-529, a human monoclonal antibody against ASGR1, completed Phase 1 clinical trial for the treatment of cardiovascular disease in 2017.

“AMG-529, a human monoclonal antibody against ASGR1, completed Phase 1 clinical trial for the treatment of cardiovascular disease in 2017.”

• cites [119] Janiszewski, 2019, A randomized, placebo-controlled, double-blind, ascending single-dose, phase 1 study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of amg 529, a novel ANTI-ASGR1 monoclonal antibody, in healthy subjects, J. Am. Coll. Cardiol. sourceNot checked yet

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

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

A study reported that Asgr1 deficiency in mice has no effect on hepatic LDLR abundance, and suggests that reduced plasma LDL-cholesterol in the absence of Asgr1 is due to increased LXRα signaling and enhanced reverse cholesterol efflux.

“However, this was recently contended by a study reporting Asgr1 deficiency in mice has no effect on hepatic LDLR abundance [88].Instead, this study suggests that reduced plasma LDL-cholesterol in the absence of Asgr1 is due to increased LXRα signaling and enhanced reverse cholesterol efflux.”

• cites [88] Wang, 2022, Inhibition of ASGR1 decreases lipid levels by promoting cholesterol excretion, Nature sourceNot checked — no full text of the source

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

The extracellular region of LDLR contains seven LDLR type A repeats, each spanning 40 amino acids, together forming the LDLR ligand-binding domain.

“The extracellular region of LDLR contains seven repeat sequences, known as LDLR type A repeats (LA) (Fig. 3).Each LA spans 40 amino acids, together forming the LDLR ligand-binding domain [105].”

• cites [105] Yamamoto, 1984, The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA, Cell sourceNot checked — no full text of the source

It may state two separate claims as one.

Berberine increases hepatic LDLR mRNA expression and reduces circulating LDL levels.

“The viability of this strategy is exemplified by the decades-long use of berberine, a plant-derived molecule that is known to increase hepatic LDLR mRNA expression and reduce circulating LDL levels [32].”

• cites [32] Kong, 2004, Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins, Nat. Med. sourceNot checked — no full text of the source

It may state two separate claims as one. The quote only partly states this claim.

miR-27a promotes expression of PCSK9, decreasing LDLR.

“miR-27a Promotes expression of PCSK9 ↓ [43,45,49]”

• cites [43] Alvarez, 2015, MicroRNA-27a decreases the level and efficiency of the LDL receptor and contributes to the dysregulation of cholesterol homeostasis, Atherosclerosis sourceNot checked yet

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

• cites [45] Goedeke, 2015, miR-27b inhibits LDLR and ABCA1 expression but does not influence plasma and hepatic lipid levels in mice, Atherosclerosis sourceNot checked yet

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

• cites [49] Yang, 2014, Identification of miR-185 as a regulator of de novo cholesterol biosynthesis and low density lipoprotein uptake, J. Lipid Res. sourceNot checked yet

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

It may state two separate claims as one.

miR-185 inhibits expression of SREBP2, decreasing LDLR.

“miR-185 Inhibits expression of SREBP2 ↓ [49]”

• cites [49] Yang, 2014, Identification of miR-185 as a regulator of de novo cholesterol biosynthesis and low density lipoprotein uptake, J. Lipid Res. sourceNot checked yet

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

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

The regulatory mechanisms detailed in this review highlight the centrality of the LDLR in cholesterol homeostasis.

“In conclusion, the regulatory mechanisms detailed in this review highlight the centrality of the LDLR in cholesterol homeostasis.”

It may state two separate claims as one.

U2-spliceosome promotes maturation of LDLR mRNA, increasing LDLR.

“U2-spliceosome Promotes maturation of LDLR mRNA ↑ [18]”

• cites [18] Zanoni, 2022, Posttranscriptional regulation of the human LDL receptor by the U2-spliceosome, Circ. Res. sourceNot checked yet

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