The DOI matches its Crossref record; 44 of the 44 references it cites were found in a registry or an index; 18 of the 28 sources its claims cite were checked for support.
Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism
Open accessAbstract
Genome-wide association studies (GWAS) have identified a genetic variant at a locus on chromosome 1p13 that is associated with reduced risk of myocardial infarction, reduced plasma levels of LDL cholesterol (LDL-C), and markedly increased expression of the gene sortilin-1 (SORT1) in liver. Sortilin is a lysosomal sorting protein that binds ligands both in the Golgi apparatus and at the plasma membrane and traffics them to the lysosome. We previously reported that increased hepatic sortilin expression in mice reduced plasma LDL-C levels. Here we show that increased hepatic sortilin not only reduced hepatic apolipoprotein B (APOB) secretion, but also increased LDL catabolism, and that both effects were dependent on intact lysosomal targeting. Loss-of-function studies demonstrated that sortilin serves as a bona fide receptor for LDL in vivo in mice. Our data are consistent with a model in which increased hepatic sortilin binds intracellular APOB-containing particles in the Golgi apparatus as well as extracellular LDL at the plasma membrane and traffics them to the lysosome for degradation. We thus provide functional evidence that genetically increased hepatic sortilin expression both reduces hepatic APOB secretion and increases LDL catabolism, providing dual mechanisms for the very strong association between increased hepatic sortilin expression and reduced plasma LDL-C levels in humans.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
Increased hepatic sortilin lowers plasma LDL-C by two lysosome-dependent mechanisms: reducing hepatic APOB secretion and increasing LDL catabolism. Sortilin binds LDL with high affinity at neutral pH and releases it at acidic pH, consistent with trafficking LDL to the lysosome.
Key findings
- Sortilin bound LDL with a Kd of approximately 2 nM at pH 7.4; LDL rapidly dissociated at acidic pH, with kd increasing from 0.004 s⁻¹ at pH 7.4 to 0.380 s⁻¹ at pH 5.0.
- Increased sortilin reduced APOB secretion by 30% in wild-type mice (P = 0.02) and 50% in Ldlr⁻/⁻ mice (P = 0.01); in primary hepatocytes, the 30% reduction was reversed by E64d (P = 0.0006), and wild-type sortilin reduced APOB secretion by 40% in HuH7 cells, while Sort.Stop and Sort.LAYA did not.
- Sortilin expression increased LDL catabolism: low- and high-dose sortilin AAV increased LDL fractional catabolic rate by 70% (P = 8 × 10⁻⁵) and 200% (P = 4 × 10⁻⁵), respectively, and increased FCR 3-fold in Ldlr⁻/⁻ mice (P = 2 × 10⁻⁵).
- Sort1 deficiency reduced LDL FCR by 40% (P = 0.002) versus wild-type and by 50% in Ldlr⁻/⁻;Sort1⁻/⁻ versus Ldlr⁻/⁻ mice (P = 0.02), but sortilin deficiency also reduced APOB secretion by 60% on the APOBEC1⁻/⁻;APOB transgenic background (P = 0.04).
Methods
- Mouse studies used AAV8-mediated hepatic overexpression of wild-type Sort1 or lysosomal-trafficking mutants (Sort.Stop, Sort.LAYA) in wild-type, Ldlr⁻/⁻, Sort1⁻/⁻, and APOBEC1⁻/⁻;APOB transgenic backgrounds; outcomes included plasma lipids, VLDL-TG and APOB secretion, and ¹²⁵I-LDL turnover.
- In vitro studies used doxycycline-inducible HuH7 hepatoma cells expressing wild-type sortilin, Sort.Stop, Sort.LAYA, or GFP, with metabolic labeling for APOB secretion, ¹²⁵I-LDL cell association/degradation assays, and immunofluorescence for LDL and LAMP1.
- Binding was measured by surface plasmon resonance with immobilized soluble human sortilin and LDL across pH 5.0–7.4; statistics used two-tailed Student’s t test and linear regression for VLDL secretion rates, with P < 0.05 considered significant.
Limitations
- Stated: the basis for reduced APOB/VLDL production in whole-body sortilin-knockout mice remains unknown; the authors suggest possible extrahepatic sortilin effects, developmental compensatory changes, or a parabolic relationship between hepatic sortilin expression and APOB secretion.
- Stated: the knockout mouse lacks sortilin in all tissues, whereas the human causal variant and the overexpression manipulations were liver-specific, so the knockout phenotype may not reflect selective hepatic sortilin deficiency.
- Evident from the text: the mechanistic evidence is from mouse and hepatoma-cell models, not direct human intervention; some supporting data are described as “data not shown,” and the human genetic association is cited rather than experimentally tested here.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
18 of 28 cited sources checked · 5 supported · 0 flagged · accuracy not yet measured
- Premisecitation
The rate of hepatic VLDL/APOB production is an important determinant of plasma LDL-C and APOB levels.
“Therefore, the rate of hepatic VLDL/APOB production is also an important determinant of plasma LDL-C and APOB levels (17,18).”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [17] Turley, 2004, Clin Cardiol. source
Checked before — its earlier verdict is held back until a new check runs.
- cites [18] Choi, 2011, Trends Endocrinol Metab. source
The section on insulin resistance and dysregulated metabolism says apoB100 is required for hepatic VLDL and LDL particles, and the section on insulin regulation links increased apoB and VLDL secretion to dyslipidemia. Our copy does not specifically establish that the rate of hepatic VLDL/apoB production is an important determinant of plasma LDL-C and apoB levels. (LLM, conf=0.78)
Experimental — accuracy not yet measured
- Premisecitation
Increasing SORT1 expression in mouse liver reduced plasma cholesterol in a variety of hyperlipidemic mouse models.
“We recently reported that increasing SORT1 expression in mouse liver reduced plasma cholesterol in a variety of hyperlipidemic mouse models, consistent with the directionality predicted by the human genetics (5)”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [5] source
- Premisecitation
Homozygosity for the minor allele at the 1p13 locus is associated with approximately 40% reduced risk for myocardial infarction.
“an approximately 40% reduced risk for myocardial infarction (MI) (1)”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [1] source
The passage on the 1p13 locus (section labeled Abstract; page unavailable) reports that the minor allele of rs599839 was associated with lower coronary artery disease risk (odds ratio 0.78). It does not report myocardial infarction risk specifically or an approximately 40% reduction among people homozygous for that allele. (LLM, conf=0.85)
Experimental — accuracy not yet measured
- Premisecitation
Homozygosity for the minor allele at the 1p13 locus is associated with a more than 10-fold increase in SORT1 expression specifically in liver.
“homozygosity for the minor allele is associated with a more than 10-fold increase in SORT1 expression specifically in liver”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [1] source
The passage on gene expression (indexed under Abstract; page unavailable) reports that rs646776 at 1p13 is strongly associated with SORT1 transcript levels in 60 human liver samples. It does not report a more than 10-fold increase in minor-allele homozygotes or establish that the association occurs specifically in liver rather than other tissues. (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Premisecitation
A sortilin knockout mouse with residual truncated sortilin expression, when fed a Western-type diet, had reduced VLDL production.
“It was previously reported that a sortilinknockout mouse that had some residual truncated sortilin expression (12), upon feeding with a Western-type diet, had reduced VLDL production (23).”
Quote in the paperNot a substantial claim1 of 2 sources checked
- Findingown data
Recombinant sortilin binds LDL particles with high affinity at neutral pH, with a Kd of approximately 2 nM at pH 7.4.
“Surface plasmon resonance (SPR) demonstrated a rapid association and slow dissociation phase between recombinant sortilin and LDL particles at neutral pH (Figure 1A).”
- Also stated in: § Sortilin demonstrates high-affinity binding to APOB in a pH-dependent manner. · plain
“quantitative analysis of the sensorgrams using a 2-state binding model yielded a K d of approximately 2 nM for the LDL-sortilin interaction at pH 7.4.”
Quote in the paperSubstantial claim - Also stated in: § Sortilin demonstrates high-affinity binding to APOB in a pH-dependent manner. · plain
- Findingown data
Wild-type sortilin expression increased LDL cell association and degradation in 293T, CHO, and ldlD cells.
“Wild-type sortilin expression was found to increase LDL cell association and degradation in 293T, CHO, and ldlD cells as well (Supplemental Figure 5, A-F).”
Quote in the paperSubstantial claim - Findingown data
Increased hepatic expression of sortilin mediates accelerated clearance of LDL from blood.
“Here, we show that increased hepatic expression of sortilin mediates accelerated clearance of LDL from blood”
Quote in the paperSubstantial claim - Findingown data
Sortilin expression reduced APOB secretion by 30% in wild-type mice (P = 0.02).
“sortilin expression reduced APOB secretion by 30% (P = 0.02; Figure 2A and Supplemental Figure 1A).”
Quote in the paperSubstantial claim - Findingown data
Human HDL and APOE DMPC discs did not bind to sortilin under the same conditions.
“In contrast, human HDL and APOE 1,2-dimyristoyl-sn-glycero-e-phosphocholine (DMPC) discs did not bind to sortilin under the same conditions (Figure 1A).”
Quote in the paperNot a substantial claim - Findingown data
Ldlr-/-;Sort1-/- mice had a 50% reduction in LDL FCR compared with Ldlr-/- mice (P = 0.02).
“Ldlr -/-;Sort1 -/-mice had a 50% reduction in FCR (P = 0.02) compared with Ldlr -/-mice”
Quote in the paperSubstantial claim - Findingown data
Only wild-type sortilin increased LDL degradation in HuH7 cells (P = 0.004).
“but only wild-type sortilin increased LDL degradation (P = 0.004; Figure 3B).”
Quote in the paperSubstantial claim - Findingown data
Sortilin demonstrates high-affinity binding to APOB.
“Sortilin demonstrates high-affinity binding to APOB.”
Quote in the paperSubstantial claim - Findingown data
Sort1 deficiency on an Ldlr-/- background was associated with a 20% reduction in plasma cholesterol.
“Sort1 deficiency on an Ldlr -/-background was associated with a 20% reduction in plasma cholesterol.”
Quote in the paperSubstantial claim - Findingown data
Sortilin expression in Ldlr-/- mice increased LDL FCR 3-fold (P = 2 × 10-5).
“Sortilin expression in these mice increased the FCR 3-fold (P = 2 × 10 -5 )”
Quote in the paperSubstantial claim - Findingown data
Clearance curves and FCRs demonstrated a dose-dependent increase in LDL clearance in wild-type mice expressing Sort1.
“Clearance curves (A) and FCRs (B) demonstrated a dose-dependent increase in LDL clearance in wild-type mice expressing Sort1.”
Quote in the paperSubstantial claim - Findingown data
LDL rapidly dissociates from sortilin at acidic pH.
“at an acidic pH, the LDL rapidly dissociated from sortilin (Figure 1B).”
Quote in the paperSubstantial claim - Findingown data
Increased expression of sortilin in the hepatocyte results in reduced hepatic production of APOB.
“We show here that increased expression of sortilin in the hepatocyte results in reduced hepatic production of APOB.”
Quote in the paperSubstantial claim - Findingown data
The reduction in hepatocyte APOB secretion by increased sortilin was completely reversed by E64d treatment (P = 0.0006).
“this effect was completely reversed by E64d treatment (P = 0.0006; Figure 2C).”
Quote in the paperSubstantial claim - Findingown data
Sortilin and LDL show strong colocalization with the lysosomal marker LAMP1.
“Sortilin and LDL show strong colocalization with the lysosomal marker LAMP1.”
Quote in the paperSubstantial claim - Findingown data
Sortilin deficiency in the hypercholesterolemic APOBEC1-/-;APOB TG background is associated with a 60% reduction in APOB secretion (P = 0.04).
“sortilin deficiency in the hypercholesterolemic APOBEC1 -/-;APOB TG background is associated with a 60% reduction in APOB secretion (P = 0.04; Figure 5F and Supplemental Figure 1B)”
Quote in the paperSubstantial claim - Findingown data
Sortilin deficiency is associated with markedly reduced LDL clearance.
“and, conversely, that sortilin deficiency is associated with markedly reduced LDL clearance.”
Quote in the paperSubstantial claim - Findingown data
Sort1-/- mice displayed a 40% reduction in LDL FCR compared with wild-type mice (P = 0.002).
“Compared with wild-type mice, Sort1 -/-mice displayed a 40% reduction in FCR (P = 0.002; Figure 4, E and F).”
Quote in the paperSubstantial claim - Findingnone given
A mutant of sortilin containing the ligand-binding domain but lacking the transmembrane domain and cytoplasmic tail did not affect LDL catabolism.
“A mutant of sortilin containing the ligandbinding domain but lacking the transmembrane domain and cytoplasmic tail did not affect LDL catabolism.”
Quote in the paperSubstantial claim - Findingown data
When crossed onto the APOBEC1-/-; APOB transgenic background, sortilin deficiency still resulted in reduced APOB production.
“Furthermore, when crossed onto the APOBEC1 -/-; APOB transgenic background, sortilin deficiency still resulted in reduced APOB production.”
Quote in the paperSubstantial claim - Findingown data
In a sortilin-knockout mouse devoid of any sortilin protein, on a chow diet, sortilin deficiency was associated with reduced APOB production.
“Using a different sortilin-knockout mouse proven to be devoid of any sortilin protein (7), we found that on a chow diet, sortilin deficiency was associated with reduced APOB production (data not shown).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [7] source
- Findingown data
Liver-associated 125I-LDL counts were 6-fold higher in mice expressing Sort.LAYA (P = 0.001).
“the liver-associated 125 I-LDL counts were 6-fold higher in mice expressing Sort.LAYA (P = 0.001, Supplemental Figure 6E)”
Quote in the paperSubstantial claim - Findingown data
Wild-type sortilin, but not Sort.Stop or Sort.LAYA, colocalized with the LAMP1 lysosomal marker when expressed in hepatoma cells.
“We found that when expressed in hepatoma cells, wild-type sortilin but not Sort.Stop or Sort.LAYA colocalized with the LAMP1 lysosomal marker (Supplemental Figure 4, A-D).”
Quote in the paperSubstantial claim - Findingcitation
An independently generated Sort1-/- mouse has a paradoxical reduction in APOB/VLDL secretion on a chow diet on both a wild-type and APOBEC1-/-;APOB Tg background.
“We further demonstrate that, consistent with a previously published report (23), an independently generated Sort1 -/-mouse has a paradoxical reduction in APOB/VLDL secretion on a chow diet on both a wild-type and APOBEC1 -/-;APOB Tg background.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [23] source
- Findingown data
Sort1 deficiency was associated with a 60% reduction in VLDL/APOB secretion on an APOBEC1-/-;APOB transgenic background.
“Sort1 deficiency was associated with a 60% reduction in VLDL/ APOB secretion on an APOBEC1 -/-;APOB transgenic background.”
Quote in the paperSubstantial claim - Findingown data
Increased sortilin expression reduced hepatocyte APOB secretion ex vivo by 30% (P = 0.009).
“increased sortilin expression reduced hepatocyte APOB secretion ex vivo by 30% (P = 0.009)”
Quote in the paperSubstantial claim - Interpretationreasoning
The identification of sortilin as an LDLR-independent pathway for LDL uptake helps explain the strong association between increased hepatic sortilin expression and reduced LDL-C levels.
“The identification of sortilin as an LDLR-independent pathway for LDL uptake helps explain the strong association between increased hepatic sortilin expression and reduced LDL-C levels.”
Quote in the paperSubstantial claim - Interpretationown data
Sortilin appears to be a key protein responsible for the previously described post-ER shunting of APOB from the Golgi to the lysosome for degradation.
“Thus, sortilin appears to be a key protein responsible for the previously described post-ER shunting of APOB from the Golgi to the lysosome for degradation.”
Quote in the paperSubstantial claim - Interpretationown data
Sortilin and the LDLR act separately to facilitate LDL uptake.
“consistent with sortilin and the LDLR acting separately to facilitate LDL uptake (Figure 4, E and F).”
Quote in the paperSubstantial claim - Interpretationown data
Sortilin requires lysosomal targeting to reduce VLDL/APOB secretion.
“consistent with sortilin requiring lysosomal targeting to reduce VLDL secretion (Figure 2, E and F).”
Quote in the paperSubstantial claim - Interpretationown data
Both reduced APOB production and increased LDL catabolism from increased hepatic sortilin expression require intact endolysosomal trafficking.
“We further demonstrate that both consequences of increased hepatic sortilin expression -reduced APOB production and increased LDL catabolism -require intact endolysosomal trafficking.”
Quote in the paperSubstantial claim - Interpretationown data
The effects of sortilin on LDL clearance were independent of the LDLR itself.
“These effects were independent of the LDLR itself.”
Quote in the paperSubstantial claim - Interpretationreasoning
Sortilin may account for the variability of residual LDL clearance in individuals with familial hypercholesterolemia.
“It may also account for the variability of residual LDL clearance in individuals with FH.”
Quote in the paperNot a substantial claim - Interpretationown data
Sortilin-mediated reductions in APOB/VLDL secretion are dependent on intact lysosomal targeting.
“Our data further indicate that the sortilin-mediated reductions in APOB/VLDL secretion are dependent on intact lysosomal targeting.”
Quote in the paperSubstantial claim - Interpretationreasoning
The dual effect of sortilin on both APOB production and LDL catabolism may explain the strong association of the SORT1 locus with reduced plasma LDL-C and APOB levels and with protection from coronary heart disease.
“This dual effect on both production and catabolism may explain the very strong association of the SORT1 locus with reduced plasma levels of LDL-C and APOB as well as with substantial protection from coronary heart disease.”
Quote in the paperSubstantial claim- Rests on an assumption: The SORT1 locus is strongly associated with reduced plasma LDL-C and APOB levels and with protection from coronary heart disease.
- Premisecitation
Increased hepatic sortilin expression in mice reduced the hepatic VLDL-triglyceride (VLDL-TG) secretion rate.
“We previously reported that increased hepatic sortilin expression in mice reduced the hepatic VLDL-triglyceride (VLDL-TG) secretion rate (5)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [5] source
- Interpretationown data
Increased hepatic sortilin expression promotes LDL catabolism in an LDLR-independent manner.
“indicating that increased hepatic sortilin expression promotes LDL catabolism in an LDLR-independent manner (Figure 4, C and D).”
Quote in the paperSubstantial claim - Premisecitation
Homozygosity for the minor allele at the 1p13 locus is associated with an average reduction of 16 mg/dl in plasma LDL-C.
“an average reduction of 16 mg/dl in plasma LDL-C”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [1] source
- It may state two separate claims as one. 37
- Probably not a substantial claim. 10
- The quote only partly states this claim. 1
It may state two separate claims as one.
Findingown dataSort.Stop was predominantly either secreted or in an intracellular, nonlysosomal location, while Sort.LAYA localized disproportionately to the plasma membrane.
“Sort.Stop was predominantly either secreted or in an intracellular, nonlysosomal location, while Sort.LAYA localized disproportionately to the plasma membrane (Supplemental Figure 4, A-D), consistent with previous observations (6).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [6] source
In “Endocytosis of chimeric receptors” (page not available), the paper reports that a sortilin-tail mutant with a disrupted YXXF motif had 2.8-fold more receptor exposed on the plasma membrane than the wild-type chimera, consistent with the Sort.LAYA observation. Our copy does not identify Sort.Stop or establish that it was predominantly secreted or in an intracellular, nonlysosomal location; the secretion results concern lysosomal enzymes, not Sort.Stop. (LLM, conf=0.84)
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.
PremisecitationSortilin localizes to the plasma membrane in clathrin-coated pits where it can function as an internalization receptor for progranulin, APOA-V, and LPL.
“Sortilin also localizes to the plasma membrane in clathrin-coated pits where it can function as an internalization receptor for progranulin (12), APOA-V (13), and LPL (ref.14 and Supplemental Figure 1B).”
Quote in the paperNot a substantial claim3 of 3 sources checked- cites [12] source
The Results section, “Rapid Sortilin-Mediated Endocytosis of PGRN to Lysosomes,” shows progranulin binding to cell-surface sortilin and being rapidly internalized. The cited paper does not establish that sortilin localizes specifically to clathrin-coated pits. APOA-V and LPL have separate citations in the citing sentence and are not attributed to this source. (LLM, conf=0.83)
Experimental — accuracy not yet measured - cites [13] source
- cites [14] source
The Results and Discussion report that sortilin is expressed on the cell surface and mediates LPL uptake and degradation. The cited paper does not establish the more specific claim that sortilin localizes to clathrin-coated pits. Progranulin and APOA-V are attributed to other references in the citing sentence. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationSortilin localizes primarily to the Golgi apparatus.
“Sortilin localizes primarily to the Golgi apparatus”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [6] source
The Introduction reports that sortilin predominates in intracellular compartments, with about 90% found in the Golgi and vesicles. The Discussion says its cytoplasmic domain conveys Golgi localization, but the copy does not establish that the Golgi apparatus alone is sortilin’s primary location. (LLM, conf=0.82)
Experimental — accuracy not yet measured
Probably not a substantial claim. It may state two separate claims as one.
PremisecitationThere are LDLR-independent mechanisms of LDL clearance from plasma, but these pathways have not been fully elucidated.
“There are LDLR-independent mechanisms of LDL clearance from plasma, but these pathways have not been fully elucidated (16).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [16] source
The Results section shows LDLR-independent LDL uptake in LDLR-deficient CHO cells, and the Discussion says further investigation of LRP6 trafficking is needed. The paper does not establish LDLR-independent clearance from plasma; its evidence is for cellular uptake, so the plasma-level claim goes beyond it. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Probably not a substantial claim.
PremisecitationGolgi-associated degradation of APOB is a more recently described pathway that may target oxidized or misfolded APOB to the lysosome for degradation prior to secretion.
“Golgi-associated degradation of APOB is a more recently described pathway that is less well understood, but may target oxidized or misfolded APOB to the lysosome for degradation prior to secretion (22)”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [22] source
The Abstract and Discussion describe apoB becoming oxidized and aggregated around Golgi exit, then being degraded through an autophagosome-lysosome pathway before secretion. The Discussion also identifies aspects of the pathway that remain unresolved. The paper does not establish that this pathway targets misfolded apoB; its mention of malfolded proteins concerns earlier quality control in the ER. (LLM, conf=0.85)
Experimental — accuracy not yet measured
It may state two separate claims as one.
PremisecitationIn humans, a common genetic variant leading to a greater than 10-fold increase in sortilin expression specifically in the liver is associated with substantially reduced plasma levels of LDL-C and APOB and with substantial reduction in coronary heart disease.
“In humans, a common genetic variant leading to a greater than 10-fold increase in sortilin expression specifically in the liver is associated with substantially reduced plasma levels of LDL-C and APOB and with substantial reduction in coronary heart disease.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [1] source
The supplied Abstract passages report that a common 1p13 variant is associated with SORT1 transcript levels in human liver and lower LDL-C; a proxy variant is also reported to be associated with lower coronary artery disease risk (odds ratio 0.78). They do not establish a greater than 10-fold increase in sortilin expression, show that the increase is specific to liver, or report reduced plasma APOB 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.
PremisecitationDuring VLDL formation in hepatocytes, APOB is lipidated initially in the ER and secondarily in the Golgi apparatus.
“During VLDL formation in hepatocytes, APOB is lipidated initially in the ER and secondarily in the Golgi apparatus (20).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [20] source
It may state two separate claims as one.
PremisecitationA genetic variant at a locus on chromosome 1p13 is associated with reduced risk of myocardial infarction, reduced plasma LDL cholesterol levels, and markedly increased expression of SORT1 in liver.
“Genome-wide association studies (GWAS) have identified a genetic variant at a locus on chromosome 1p13 that is associated with reduced risk of myocardial infarction, reduced plasma levels of LDL cholesterol (LDL-C), and markedly increased expression of the gene sortilin-1 (SORT1) in liver.”
- Also stated in: § Introduction · plain
“Among the loci most strongly associated with LDL cholesterol (LDL-C) is a novel locus on chromosome 1p13 (P = 10 -170 ) harboring several genes including SORT1.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [1] source
The passages labeled Abstract report that minor alleles at 1p13 lower LDL cholesterol and that rs646776 is strongly associated with SORT1 transcript levels in human liver; they also describe increased sortilin expression with its C allele. The paper reports lower risk of coronary artery disease for the LDL-lowering allele of a proxy SNP, but does not specifically report reduced myocardial infarction risk. No page numbers are provided for these passages. (LLM, conf=0.86)
Experimental — accuracy not yet measured
- Rests on an assumption: The association between the chromosome 1p13 locus and reduced LDL-C and myocardial infarction risk is mediated specifically by increased hepatic SORT1 expression rather than by other genes at the locus.
- Also stated in: § Introduction · plain
Probably not a substantial claim.
PremisecitationVLDL/APOB production is regulated mainly via posttranslational control.
“VLDL/APOB production is regulated mainly via posttranslational control (19).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [19] source
The Concluding Remarks (page not specified) say that major regulatory pathways involve degradation of apoB or VLDL rather than changes in apoB synthesis. But the Abstract (page not specified) identifies both cotranslational and posttranslational targeting for degradation, so the source does not establish that control is mainly posttranslational. (LLM, conf=0.84)
Experimental — accuracy not yet measured
It may state two separate claims as one.
PremisecitationSortilin is a lysosomal sorting protein that binds ligands both in the Golgi apparatus and at the plasma membrane and traffics them to the lysosome.
“Sortilin is a lysosomal sorting protein that binds ligands both in the Golgi apparatus and at the plasma membrane and traffics them to the lysosome.”
- Also stated in: § Introduction · plain
“Sortilin localizes primarily to the Golgi apparatus and has been shown to bind a variety of ligands and traffic them from the Golgi apparatus to the lysosome (6)(7)(8)(9)(10)(11).”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [6] source
The Introduction describes sortilin as a candidate sorting receptor for ligands in the synthetic pathway and at the cell surface. The ‘Motifs for sortilin internalization’ section reports transport to lysosomes from both routes, but the experiment used a chimera with sortilin’s tail and another receptor’s ligand-binding domain. It supports a sorting role for full-length sortilin without directly showing that native sortilin binds ligands in both locations and carries them to lysosomes. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [7] source
- cites [8] source
- Also stated in: § Introduction · plain
It may state two separate claims as one.
Findingown dataCompared with cells containing only endogenous sortilin, wild-type sortilin increases intracellular LDL, while Sort.Stop does not increase intracellular LDL.
“Compared with cells containing only endogenous sortilin (C), wild-type sortilin (D) increases intracellular LDL, while Sort.Stop (E) does not increase intracellular LDL.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataDox-mediated induction of wild-type Sort1 led to a 40% reduction in APOB secretion in HuH7 cells, whereas induction of GFP, Sort.Stop, and Sort.LAYA had no effect.
“dox-mediated induction of wild-type Sort1 led to a 40% reduction in APOB secretion, whereas induction of GFP, Sort.Stop, and Sort.LAYA had no effect on APOB secretion”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataBoth the reduction in APOB production and the increase in LDL catabolism are dependent on lysosomal targeting.
“Furthermore, we show that both effects are dependent on lysosomal targeting, consistent with sortilin's role as a lysosomal trafficking protein.”
Quote in the paperSubstantial claim- Rests on an assumption: Sortilin functions as a lysosomal trafficking protein.
It may state two separate claims as one.
Findingown dataSort.LAYA reduced plasma total and LDL-C and increased LDL clearance from plasma in Ldlr-/- mice.
“In contrast, Sort.LAYA reduced plasma total and LDL-C (Supplemental Figure 6, A-D) and increased LDL clearance from plasma (Figure 4, C and D).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingnone givenA different mutant of sortilin containing the ligand binding and transmembrane domains but with mutations in the cytoplasmic tail that preclude lysosomal targeting was capable of binding LDL and mediating its clearance from blood, but incapable of delivering it to the lysosome for degradation.
“Moreover, a different mutant of sortilin containing the ligand binding and transmembrane domains but with mutations in the cytoplasmic tail that preclude lysosomal targeting was capable of binding LDL and mediating its clearance from blood, but incapable of delivering it to the lysosome for degradation.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataSort1 deficiency on an APOBEC1-/-;APOB transgenic background did not affect plasma cholesterol or APOB levels.
“Sort1 deficiency on an APOBEC1 -/-;APOB transgenic background did not affect plasma cholesterol or APOB levels.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataBoth wild-type sortilin and Sort.LAYA increased 125I-LDL cell association 5-fold, while only wild-type sortilin increased 125I-LDL degradation.
“Both wild-type sortilin and Sort.LAYA increased 125 I-LDL cell association 5-fold, while only wild-type sortilin increased 125 I-LDL degradation.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataSort.LAYA resulted in profound accumulation of LDL at the cell surface without increasing intracellular LDL.
“Sort.LAYA (F) resulted in profound accumulation of LDL at the cell surface without increasing intracellular LDL”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataThere is a 40% reduction in FCR in Sort1-/- mice compared with wild-type mice and a 50% reduction in FCR in Ldlr-/-;Sort1-/- mice compared with Ldlr-/- mice.
“Clearance and FCRs demonstrating a 40% reduction in FCR in Sort1 -/-mice compared with wild-type mice and a 50% reduction in FCR in Ldlr -/-;Sort1 -/-mice compared with Ldlr -/-mice.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataSortilin expression promotes LDL uptake and lysosomal catabolism in vivo.
“Sortilin expression promotes LDL uptake and lysosomal catabolism in vivo.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataWildtype sortilin and Sort.LAYA increased LDL clearance, while Sort.Stop did not increase plasma LDL clearance.
“Clearance curves (C) and FCRs (D) demonstrated that wildtype sortilin and Sort.LAYA increased LDL clearance, while Sort.Stop did not increase plasma LDL clearance”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Findingown dataSortilin expression reduced APOB secretion by 50% in Ldlr-/- mice (P = 0.01).
“expression reduced APOB secretion by 50% (P = 0.01; Figure 2B and Supplemental Figure 2).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataSort1-deficient mice were not hypercholesterolemic, either on the Ldlr-/- background or on an APOBEC1-/-;APOB TG background.
“despite the substantially reduced catabolism of LDL in Sort1-deficient mice, we noted that they were not hypercholesterolemic, either on the Ldlr -/-background or on an 5, A-E).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataBoth wild-type sortilin and Sort.LAYA increased LDL cell association 5-fold in HuH7 cells (P = 1.39 × 10-8 and P = 3.51 × 10-6).
“Both wild-type sortilin and Sort.LAYA increased LDL cell association 5-fold (P = 1.39 × 10 -8 and P = 3.51 × 10 -6 ; Figure 3A)”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataIn wild-type mice, low and high doses of sortilin AAV increased LDL fractional catabolic rate (FCR) by 70% (P = 8 × 10-5) and 200% (P = 4 × 10-5), respectively.
“mice injected with low and high doses of sortilin AAV had an increase of 70% (P = 8 × 10 -5 ) and 200% (P = 4 × 10 -5 ) in fractional catabolic rate (FCR), respectively (Figure 4, A and B).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataSortilin deficiency is associated with reduced or normal plasma cholesterol and reduced APOB/VLDL secretion.
“Sortilin deficiency is associated with reduced or normal plasma cholesterol and reduced APOB/VLDL secretion.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataSortilin expression promotes LDL uptake and lysosomal catabolism in vitro.
“Sortilin expression promotes LDL uptake and lysosomal catabolism in vitro.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataSort.Stop had no significant effects on LDL cell association or degradation.
“Sort.Stop had no significant effects on LDL cell association or degradation (Figure 3, A and B).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataSort.Stop did not increase 125I-LDL cell association or degradation.
“Sort.Stop did not increase 125 I-LDL cell association or degradation”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataSortilin binds LDL with high affinity at neutral pH and with much less affinity at acidic pH, consistent with release in the endosome.
“We demonstrate that sortilin binds LDL with high affinity at neutral pH and with much less affinity at acidic pH, consistent with release in the endosome.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataSort.Stop had no effect on plasma lipid levels or LDL catabolism in Ldlr-/- mice.
“Sort.Stop was well expressed, but had no effect on plasma lipid levels or LDL catabolism.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataWild-type sortilin reduced VLDL secretion rate by 30% (P = 0.002) in Ldlr-/- mice, while neither Sort.Stop nor Sort.LAYA affected VLDL secretion.
“while wildtype sortilin reduced the secretion rate by 30% (P = 0.002) as previously observed, neither of the sortilin trafficking mutants affected VLDL secretion (Figure 2D)”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataComplete deficiency of sortilin results in delayed LDL catabolism and reduced APOB secretion with offsetting effects on LDL-C levels.
“complete deficiency of sortilin results in delayed LDL catabolism and reduced APOB secretion with offsetting effects on LDL-C levels.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenAll animal protocols were reviewed and approved by the University of Pennsylvania IACUC.
“All animal protocols were reviewed and approved by the University of Pennsylvania IACUC.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Interpretationown dataIncreased sortilin expression reduces plasma LDL-C both by reducing the hepatic production of APOB and by increasing the catabolism of LDL.
“Here, we provide evidence in mice and hepatocytes that increased sortilin expression reduces plasma LDL-C both by reducing the hepatic production of APOB and by increasing the catabolism of LDL (Supplemental Figure 7).”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationWhen there is insufficient lipidation of nascent APOB in the ER, APOB undergoes ER-associated degradation (ERAD), which is mediated by the proteasome.
“When there is insufficient lipidation of nascent APOB in the ER, APOB undergoes ER-associated degradation (ERAD), which is mediated by the proteasome (21).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [21] source
Checked before — its earlier verdict is held back until a new check runs.
It may state two separate claims as one.
Interpretationown dataBoth increased hepatic sortilin expression and total-body sortilin deficiency are associated with reduced VLDL/APOB production.
“Thus, both increased hepatic sortilin expression and total-body sortilin deficiency are associated with reduced VLDL/APOB production.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataThe reduced APOB secretion in sortilin-deficient mice offsets the reduced LDL catabolism and results in an unremarkable plasma lipid profile.
“offsetting the reduced LDL catabolism and resulting in the unremarkable plasma lipid profile.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataIncreased hepatic expression of sortilin results in both increased LDL catabolism and reduced APOB secretion with additive effects in reducing LDL-C levels.
“Thus, while increased hepatic expression of sortilin results in both increased LDL catabolism and reduced APOB secretion with additive effects in reducing LDL-C levels”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown dataLDL binding to an activated but uncoated CM3 chip was negligible, serving as a control for nonspecific binding.
“LDL was flowed across an activated but uncoated CM3 chip under the same conditions as control for nonspecific binding, and this was found to be negligible.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Interpretationown dataSort.LAYA acts as a cell-surface reservoir for LDL binding, but fails to target LDL to the lysosome for degradation.
“This is consistent with the in vitro LDL imaging studies suggesting that Sort.LAYA acts as a cell-surface reservoir for LDL binding, but fails to target the LDL to the lysosome for degradation.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
PremisecitationLDL is catabolized by the liver via the LDL receptor (LDLR), which binds APOB and removes LDL from circulation and traffics it to the endosomal system for degradation.
“LDL is catabolized by the liver via the LDL receptor (LDLR), which binds APOB and removes LDL from circulation and traffics it to the endosomal system for degradation (15).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [15] source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationThe minor allele frequency of the most strongly associated SNP at the 1p13 locus is approximately 25%.
“The minor allele frequency of the most strongly associated SNP is approximately 25%”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1] source
It may state two separate claims as one.
Interpretationown dataIncreased hepatic expression of sortilin, as seen in humans carrying a common variant at the SORT1 locus, is associated with both reduced hepatic APOB production and increased LDL catabolism.
“In summary, we present evidence that increased hepatic expression of sortilin, as seen in humans carrying a common variant at the SORT1 locus, is associated with both reduced hepatic APOB production and increased LDL catabolism.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataThe binding data are consistent with binding of LDL to sortilin at the cell surface and Golgi apparatus and dissociation of LDL from sortilin in the endosomal compartment.
“These data are consistent with binding of LDL to sortilin at the cell surface and Golgi apparatus and dissociation of LDL from sortilin in the endosomal compartment.”
Quote in the paperSubstantial claim
The paper relies on this without support.
The association between the chromosome 1p13 locus and reduced LDL-C and myocardial infarction risk is mediated specifically by increased hepatic SORT1 expression rather than by other genes at the locus.
“harboring several genes including SORT1”
“markedly increased expression of the gene sortilin-1 (SORT1) in liver”
The paper relies on this without support.
Sortilin functions as a lysosomal trafficking protein.
“consistent with sortilin's role as a lysosomal trafficking protein.”
The paper relies on this without support.
The SORT1 locus is strongly associated with reduced plasma LDL-C and APOB levels and with protection from coronary heart disease.
“the very strong association of the SORT1 locus with reduced plasma levels of LDL-C and APOB as well as with substantial protection from coronary heart disease.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The increased ApoB concentrations caused by hepatic (P)RR inhibition are likely a result of reduced sortilin-1 abundance.
“Since sortilin-1 promotes ApoB degradation and the (P)RR inhibition reduces sortilin-1 abundance (6, 7, 26), increased ApoB is likely a result of reduced sortilin-1 abundance.”
From (Pro)renin Receptor Inhibition Reduces Plasma Cholesterol and Triglycerides but Does Not Attenuate Atherosclerosis in Atherosclerotic Mice (2021) · cites this paper as [26]
The Discussion (page not available) says sortilin promotes lysosomal degradation of APOB and reports that disrupting liver sortilin expression can increase APOB/VLDL secretion. This supports the proposed mechanism, but the paper does not examine (P)RR inhibition or establish that it reduces sortilin abundance and thereby raises APOB. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIn the liver, sortilin acts as a lipoprotein receptor controlling hepatic uptake and release of cholesterol-rich lipoproteins, explaining genome-wide association of SORT1 with plasma cholesterol levels and risk of myocardial infarction.
“In the liver, it acts as a lipoprotein receptor controlling hepatic uptake but also release of cholesterol-rich lipoproteins, explaining genome-wide association of the encoding gene SORT1 with plasma cholesterol levels and the risk of myocardial infarction2,3,7–9”
From Interaction of sortilin with apolipoprotein E3 enables neurons to use long-chain fatty acids as alternative metabolic fuel (2025) · cites this paper as [8]
The Abstract and Discussion report that hepatic sortilin reduces APOB secretion and increases LDL catabolism, supporting the claim about lipoprotein release and uptake. The Introduction links a SORT1 variant to lower LDL cholesterol and reduced myocardial infarction risk. The Discussion says the dual mechanism *may explain* the association with coronary heart disease; it does not establish that it explains the risk association. (LLM, conf=0.83)
Experimental — accuracy not yet measuredSORT1 is a hepatic clearance receptor for LDL that also regulates VLDL secretion and plasma triglycerides.
“SORT1 is a recently identified hepatic clearance receptor for LDL, which also regulates VLDL secretion and plasma triglycerides.16,20–22,38”
From (Pro)renin Receptor Inhibition Reprograms Hepatic Lipid Metabolism and Protects Mice From Diet-Induced Obesity and Hepatosteatosis (2018) · cites this paper as [22]
The Discussion identifies hepatic sortilin as an LDLR-independent pathway for LDL clearance, and the VLDL secretion results report that sortilin expression reduced VLDL-triglyceride secretion by 30%. Our copy does not establish that SORT1 regulates circulating plasma triglyceride levels; a secretion-rate measurement is not the same as a plasma-level finding. No page numbers were provided for these passages. (LLM, conf=0.84)
Experimental — accuracy not yet measuredOverexpression of SORT1 increases LDL clearance and decreases plasma LDL levels.
“Overexpression of SORT1 increases LDL clearance and decreases plasma LDL levels,16,21,22”
From (Pro)renin Receptor Inhibition Reprograms Hepatic Lipid Metabolism and Protects Mice From Diet-Induced Obesity and Hepatosteatosis (2018) · cites this paper as [22]
Hepatocyte sortilin modulates very low density lipoprotein (VLDL) secretion.
“In addition to facilitating PCSK9 secretion, hepatocyte sortilin has been shown to modulate very low density lipoprotein (VLDL) secretion;66–70”
From EHBP1 suppresses liver fibrosis in metabolic dysfunction-associated steatohepatitis (2025) · cites this paper as [69]
SORT1 deficiency reduces cellular LDL uptake in vitro and LDL clearance in vivo.
“whereas SORT1 deficiency reduces cellular LDL up-take in vitro and LDL clearance in vivo.22,23”
From (Pro)renin Receptor Inhibition Reprograms Hepatic Lipid Metabolism and Protects Mice From Diet-Induced Obesity and Hepatosteatosis (2018) · cites this paper as [22]
Overexpressing SORT1 promotes ApoB degradation via an endolysosome-dependent route and reduces VLDL secretion and plasma triglyceride levels.
“Overexpressing SORT1 promotes ApoB degradation via an endolysosome-dependent route and hence reduces VLDL secretion and plasma triglyceride levels.22”
From (Pro)renin Receptor Inhibition Reprograms Hepatic Lipid Metabolism and Protects Mice From Diet-Induced Obesity and Hepatosteatosis (2018) · cites this paper as [22]
SORT1, located within the 1p13.3 region, is a novel regulator of LDL metabolism.
“Subsequent mechanistic studies revealed that SORT1 (sortilin-1), located within the 1p13.3 region, is a novel regulator of LDL metabolism.20–22”
From (Pro)renin Receptor Inhibition Reprograms Hepatic Lipid Metabolism and Protects Mice From Diet-Induced Obesity and Hepatosteatosis (2018) · cites this paper as [22]
Mice deficient for SORT1 display reduced VLDL secretion and triglyceride levels.
“Controversially, mice deficient for SORT1 also display reduced VLDL secretion and triglyceride levels.20,22”
From (Pro)renin Receptor Inhibition Reprograms Hepatic Lipid Metabolism and Protects Mice From Diet-Induced Obesity and Hepatosteatosis (2018) · cites this paper as [22]
hSORT1 overexpression reversed the (P)RR inhibition-induced increase in plasma cholesterol levels, primarily by decreasing cholesterol content in the VLDL and IDL/LDL fractions.
“Given that SORT1 itself is a clearance receptor for LDL,20–22 it is not surprising that hSORT1 overexpression reversed the (P) RR inhibition–induced increase in plasma cholesterol levels, primarily by decreasing the cholesterol content in the VLDL and IDL/LDL fractions (Figure 3A and 3B).”
From (Pro)renin Receptor Inhibition Reprograms Hepatic Lipid Metabolism and Protects Mice From Diet-Induced Obesity and Hepatosteatosis (2018) · cites this paper as [22]
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.
Figure 1B LDL concentration conflicts with the SPR methods
MinorFigure 1B states that LDL was applied at 100 μg/μl, equivalent to 100,000 μg/ml. The SPR methods give an LDL concentration range of only 10 to 300 μg/ml.
“100 μg/μl of LDL was bound to immobilized human sortilin in HBS-EP buffer at pH 7.4.”
“To monitor LDL association with sortilin, LDL (isolated by sequential ultracentrifugation from human plasma as described before; ref. 40) solutions in HBS-EP buffer (Biacore) (0.01 M Hepes, 0.15 M NaCl, 3 mM EDTA, 0.005% surfactant P20, pH 7.4) in the concentration range of 10 to 300 μg/ml were flowed across the chip at 20 μl/min for 4 minutes at room temperature.”
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Self-citation
Metadata
- Authors
- Strong, A., Ding, Q., Edmondson, A. C., Millar, J. S., Sachs, K. V., Li, X., Kumaravel, A., Wang, M. Y., Ai, D., Guo, L., Alexander, E. T., Nguyen, D., Lund-Katz, S., Phillips, M. C., Morales, C. R., Tall, A. R., Kathiresan, S., Fisher, E. A., Musunuru, K., & Rader, D. J.
- Affiliations
- University of Pennsylvania (US)
- Harvard University (US)
- Columbia University Irving Medical Center (US)
- Children's Hospital of Philadelphia (US)
- Massachusetts General Hospital (US)
- Corresponding author
- Rader, Daniel J.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2012-08-01
- Volume
- 122
- Issue
- 8
- Pages
- 2807-2816
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3408750
- OpenAlex
- W2071039886
- Cited by
- 222
- References
- 41
- Citations by year
- 2026: 11 · 2025: 5 · 2024: 5 · 2023: 8 · 2022: 19 · 2021: 15 · 2020: 13 · 2019: 20 · 2018: 11 · 2017: 23 · 2016: 18 · 2015: 23 · 2014: 29 · 2013: 15 · 2012: 7
- FWCI
- 9.39
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- University of Pennsylvania
- Strong
- National Heart, Lung, and Blood Institute (RC2HL101864, R01HL109489, K99HL098364)
- 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
- sortilin, SORT1, apolipoprotein B secretion, LDL catabolism, LDL receptor, lysosomal targeting, hepatic lipid metabolism, LDL cholesterol, myocardial infarction risk, Golgi apparatus, lysosomal degradation
- MeSH terms
- APOBEC-1 Deaminase, Sortilin, Animals, Apolipoproteins B, Base Sequence, Cell Line, Cytidine Deaminase, Humans, Hydrogen-Ion Concentration, Kinetics, Lipoproteins, LDL, Lipoproteins, VLDL, Liver, Lysosomes, Mice, Transgenic, Models, Biological, Receptors, LDL, Recombinant Proteins, Mutagenesis, Site-Directed, DNA Primers, Mice, Knockout, Adaptor Proteins, Vesicular Transport, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-11-08, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-11-08 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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