The DOI matches its Crossref record; 45 of the 45 references it cites were found in a registry or an index; 23 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
44 Own result · 18 Own interpretation · 13 Partly supported · 5 Supported · 3 No full text of the sources · 2 Own method · 2 No basis given · 1 Supported so far · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Therefore, the rate of hepatic VLDL/APOB production is also an important determinant of plasma LDL-C and APOB levels (17,18).”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Introduction
What the sources say
- Partly supportedcites [17] Turley, 2004, Clin Cardiol. sourceExperimental — accuracy not yet measured
The liver-regulation passage (labeled Abstract; page not provided) says hepatic VLDL are precursors of most circulating LDL and that changes in LDL production can alter plasma LDL-C. It therefore supports the LDL-C part of the claim, but it does not state that hepatic APOB production determines plasma APOB levels; the only apolipoprotein B mention found is in a reference title. (LLM, conf=0.88)
- Partly supportedcites [18] Choi, 2011, Trends Endocrinol Metab. sourceExperimental — accuracy not yet measured
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)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“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)”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Introduction
What the sources say
- Supportedcites [5] source
In “Sort1 in Mouse Liver Alters Plasma Lipids,” the paper reports that liver-specific Sort1 overexpression markedly reduced total plasma cholesterol in Apobec1−/−; APOB Tg mice, with consistent results in three other mouse backgrounds. It also says these mouse findings were concordant with the direction of the human genetic findings. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“an approximately 40% reduced risk for myocardial infarction (MI) (1)”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Introduction
What the sources say
- Partly supportedcites [1] sourceExperimental — accuracy not yet measured
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)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“We previously reported that increased hepatic sortilin expression in mice reduced the hepatic VLDL-triglyceride (VLDL-TG) secretion rate (5)”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Introduction
What the sources say
- Supportedcites [5] source
In “Sort1 in Mouse Liver Alters Plasma Lipids,” the paper reports that liver-targeted Sort1 overexpression in mice reduced the measured rates of both VLDL secretion and triglyceride secretion. This supports the citing sentence’s description of reduced hepatic VLDL-TG secretion. (LLM, conf=0.93)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“an average reduction of 16 mg/dl in plasma LDL-C”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Introduction
What the sources say
- Partly supportedcites [1] sourceExperimental — accuracy not yet measured
The passage on the two LDL-cholesterol loci (indexed under Abstract; page unavailable) reports a reduction of approximately 5–8 mg/dl per minor-allele copy at 1p13. It assigns the approximately 16 mg/dl reduction for two minor-allele copies to a different locus, 19p13, so it does not establish 16 mg/dl as the average reduction for homozygosity at 1p13. (LLM, conf=0.86)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“homozygosity for the minor allele is associated with a more than 10-fold increase in SORT1 expression specifically in liver”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Introduction
What the sources say
- Partly supportedcites [1] sourceExperimental — accuracy not yet measured
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)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“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).”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Discussion
What the sources say
- Supportedcites [12] source
The Experimental Procedures section (“Sort1−/− and GRN−/− mice”) says the knockout strain has trace levels of smaller-sized mutant sortilin protein, although none folds properly or reaches the cell surface. This supports the part attached to citation (12); the Western-type diet and VLDL-production finding is attached to citation (23), not this source. (LLM, conf=0.90)
- Not checked — no full text of the sourcecites [23] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Sortilin demonstrates high-affinity binding to APOB in a pH-dependent manner.
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Sortilin demonstrates high-affinity binding to APOB in a pH-dependent manner. · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Sortilin demonstrates high-affinity binding to APOB in a pH-dependent manner.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Here, we show that increased hepatic expression of sortilin mediates accelerated clearance of LDL from blood”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 37
- Probably not a substantial claim. 10
- The quote only partly states this claim. 1
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Sortilin demonstrates high-affinity binding to APOB in a pH-dependent manner.
What the sources say
- Partly supportedcites [6] sourceExperimental — accuracy not yet measured
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)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Introduction
What the sources say
- Partly supportedcites [12] sourceExperimental — accuracy not yet measured
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)
- Supportedcites [13] source
Citation 13 is attached to the APOA-V example, not to progranulin or LPL. The Discussion (page unavailable) reports that APOA-V binds sortilin on cell surfaces and is rapidly internalized, supporting sortilin's role as an APOA-V internalization receptor. (LLM, conf=0.91)
- Partly supportedcites [14] sourceExperimental — accuracy not yet measured
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)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“When there is insufficient lipidation of nascent APOB in the ER, APOB undergoes ER-associated degradation (ERAD), which is mediated by the proteasome (21).”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Introduction
What the sources say
- Supportedcites [21] source
The Discussion states that limited lipid availability impedes nascent apoB translocation across the ER membrane and promotes ubiquitination and cytosolic degradation through the ubiquitin–proteasome pathway. The paper also describes this as a quality-control route for eliminating lipid-challenged nascent apoB. (LLM, conf=0.93)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Sortilin localizes primarily to the Golgi apparatus”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Introduction
What the sources say
- Partly supportedcites [6] sourceExperimental — accuracy not yet measured
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)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“There are LDLR-independent mechanisms of LDL clearance from plasma, but these pathways have not been fully elucidated (16).”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Introduction
What the sources say
- Partly supportedcites [16] sourceExperimental — accuracy not yet measured
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)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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)”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Introduction
What the sources say
- Partly supportedcites [22] sourceExperimental — accuracy not yet measured
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)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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.”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Discussion
What the sources say
- Partly supportedcites [1] sourceExperimental — accuracy not yet measured
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)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“During VLDL formation in hepatocytes, APOB is lipidated initially in the ER and secondarily in the Golgi apparatus (20).”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Introduction
What the sources say
- Supportedcites [20] source
The Introduction says apoB-100 recruits lipids as hepatic VLDL assembly begins in the ER. The Concluding remarks and perspectives (Figure 2) describe subsequent TAG addition to the apoB-lipid particle and VLDL maturation through ER/Golgi trafficking; the Non-apoB apolipoproteins section also refers to assembly within the Golgi apparatus. Together, these support the cited sentence’s two-stage description. (LLM, conf=0.84)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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.”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Abstract
What the sources say
- Partly supportedcites [1] sourceExperimental — accuracy not yet measured
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)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- 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
Every source the paper cites for this claim was checked and supports it.
In the paper
“The minor allele frequency of the most strongly associated SNP is approximately 25%”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Introduction
What the sources say
- Supportedcites [1] source
The passage on the 1p13 locus reports that rs646776 has the stronger LDL-cholesterol association of the two SNPs (combined P = 3 × 10−29 versus 3 × 10−21 for rs599839) and that the minor allele at either SNP has a 24% frequency. That supports the claim’s approximation of 25%. (LLM, conf=0.94)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“VLDL/APOB production is regulated mainly via posttranslational control (19).”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Introduction
What the sources say
- Partly supportedcites [19] sourceExperimental — accuracy not yet measured
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)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Abstract
What the sources say
- Partly supportedcites [6] sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [7] source
- Supportedcites [8] source
The paper describes sortilin as both a cell-surface receptor for ligands and an intracellular chaperone. Its Discussion states that sortilin has sorting motifs for trafficking between the trans-Golgi network and late endosomes and for internalization from the plasma membrane; the paper also reports sortilin-dependent delivery of BDNF to the lysosome. (LLM, conf=0.87)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Also stated in: § Introduction · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Compared with cells containing only endogenous sortilin (C), wild-type sortilin (D) increases intracellular LDL, while Sort.Stop (E) does not increase intracellular LDL.”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > SPR studies.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Sortilin demonstrates high-affinity binding to APOB in a pH-dependent manner.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Furthermore, we show that both effects are dependent on lysosomal targeting, consistent with sortilin's role as a lysosomal trafficking protein.”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Discussion
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Sortilin functions as a lysosomal trafficking protein.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Sortilin demonstrates high-affinity binding to APOB in a pH-dependent manner.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Sort1 deficiency on an APOBEC1 -/-;APOB transgenic background did not affect plasma cholesterol or APOB levels.”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > SPR studies.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > SPR studies.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Sort.LAYA (F) resulted in profound accumulation of LDL at the cell surface without increasing intracellular LDL”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > SPR studies.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > SPR studies.
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Sortilin expression promotes LDL uptake and lysosomal catabolism in vivo.”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > SPR studies.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > SPR studies.
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“expression reduced APOB secretion by 50% (P = 0.01; Figure 2B and Supplemental Figure 2).”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Sortilin demonstrates high-affinity binding to APOB in a pH-dependent manner.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The quote only partly states this claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Sortilin demonstrates high-affinity binding to APOB in a pH-dependent manner.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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)”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Sortilin demonstrates high-affinity binding to APOB in a pH-dependent manner.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Sortilin demonstrates high-affinity binding to APOB in a pH-dependent manner.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Sortilin deficiency is associated with reduced or normal plasma cholesterol and reduced APOB/VLDL secretion.”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > SPR studies.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Sortilin expression promotes LDL uptake and lysosomal catabolism in vitro.”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > SPR studies.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Sort.Stop had no significant effects on LDL cell association or degradation (Figure 3, A and B).”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Sortilin demonstrates high-affinity binding to APOB in a pH-dependent manner.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Sort.Stop did not increase 125 I-LDL cell association or degradation”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > SPR studies.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Discussion
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Sort.Stop was well expressed, but had no effect on plasma lipid levels or LDL catabolism.”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Sortilin demonstrates high-affinity binding to APOB in a pH-dependent manner.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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)”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Sortilin demonstrates high-affinity binding to APOB in a pH-dependent manner.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“complete deficiency of sortilin results in delayed LDL catabolism and reduced APOB secretion with offsetting effects on LDL-C levels.”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Sortilin demonstrates high-affinity binding to APOB in a pH-dependent manner.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All animal protocols were reviewed and approved by the University of Pennsylvania IACUC.”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Study approval.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Discussion
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, both increased hepatic sortilin expression and total-body sortilin deficiency are associated with reduced VLDL/APOB production.”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“offsetting the reduced LDL catabolism and resulting in the unremarkable plasma lipid profile.”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Sortilin demonstrates high-affinity binding to APOB in a pH-dependent manner.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Sortilin demonstrates high-affinity binding to APOB in a pH-dependent manner.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > SPR studies.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Sortilin demonstrates high-affinity binding to APOB in a pH-dependent manner.
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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).”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Introduction
What the sources say
- Not checked — no full text of the sourcecites [15] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > Sortilin demonstrates high-affinity binding to APOB in a pH-dependent manner.
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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 source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measured
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
In the citing paper
“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]
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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > SPR studies.
“100 μg/μl of LDL was bound to immobilized human sortilin in HBS-EP buffer at pH 7.4.”
§ Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism > SPR studies.
“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.”
Citations
Cites
A Receptor-Mediated Pathway for Cholesterol Homeostasis
Brown, M. S., & Goldstein, J. L. (1986) · Science · doi:10.1126/science.3513311 · Cited by 5,703
Biological, clinical and population relevance of 95 loci for blood lipids
Teslovich, T. M., Musunuru, K., Smith, A. V., Edmondson, A. C., Stylianou, I. M., Koseki, M., Pirruccello, J. P., Ripatti, S., Chasman, D. I., Willer, C. J., et al. (2010) · Nature · doi:10.1038/nature09270 · Cited by 3,487
Self-citationthe GIANT Consortium (2009) · Nature Genetics · doi:10.1038/ng.287 · Cited by 1,720
Kathiresan, S., Melander, O., Guiducci, C., Surti, A., Burtt, N. P., Rieder, M. J., Cooper, G. M., Roos, C., Voight, B. F., Havulinna, A. S., et al. (2008) · Nature Genetics · doi:10.1038/ng.75 · Cited by 1,386
Self-citationCommon variants at 30 loci contribute to polygenic dyslipidemia
Kathiresan, S., Willer, C. J., Peloso, G. M., Demissie, S., Musunuru, K., Schadt, E. E., Kaplan, L., Bennett, D., Li, Y., Tanaka, T., et al. (2009) · Nature Genetics · doi:10.1038/ng.291 · Cited by 1,364
Self-citationGoldstein, J. L., & Brown, M. S. (2009) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.108.179564 · Cited by 1,344
From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus
Musunuru, K., Strong, A., Frank-Kamenetsky, M., Lee, N. E., Ahfeldt, T., Sachs, K. V., Li, X., Li, H., Kuperwasser, N., Ruda, V. M., et al. (2010) · Nature · doi:10.1038/nature09266 · Cited by 1,140
Self-citationSortilin-Mediated Endocytosis Determines Levels of the Frontotemporal Dementia Protein, Progranulin
Hu, F., Padukkavidana, T., Vægter, C. B., Brady, O. A., Zheng, Y., Mackenzie, I. R., Feldman, H. H., Nykjaer, A., & Strittmatter, S. M. (2010) · Neuron · doi:10.1016/j.neuron.2010.09.034 · Cited by 536
Nielsen, M. S., Madsen, P., Christensen, E. I., Nykjær, A., Gliemann, J., Kasper, D., Pohlmann, R., & Petersen, C. M. (2001) · The EMBO Journal · doi:10.1093/emboj/20.9.2180 · Cited by 457
Rohlmann, A., Gotthardt, M., Hammer, R. E., & Herz, J. (1998) · Journal of Clinical Investigation · doi:10.1172/jci1240 · Cited by 455 · cited 1×
“To date, several additional receptors have been reported to facilitate clearance of TG-rich lipoproteins, including heparan-sulfate proteoglycans (HSPGs) (29), LDLR-related protein-1 (LRP1) (30), and syndecan-1 (31).”
Background
Research works printed but not linked: 2
- Stanford, 2009, J Clin Invest., 119, 3236
- Grundy, 1990, Dis Mon., 36, 641
Cited by
Sorted by citations
Opportunities and challenges for transcriptome-wide association studies
Wainberg, M., Sinnott-Armstrong, N., Mancuso, N., Barbeira, A., Knowles, D. A., Golan, D., Ermel, R., Ruusalepp, A., Quertermous, T., Hao, K., et al. (2019) · Nature Genetics · doi:10.1038/s41588-019-0385-z · Cited by 906
Genetics of coronary artery disease: discovery, biology and clinical translation
Khera, A. V., & Kathiresan, S. (2017) · Nature Reviews Genetics · doi:10.1038/nrg.2016.160 · Cited by 659
Self-citationNew insights into the pathophysiology of dyslipidemia in type 2 diabetes
Taskinen, M.-R., & Borén, J. (2015) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2015.01.039 · Cited by 440
A statistical framework for cross-tissue transcriptome-wide association analysis
Hu, Y., Li, M., Lu, Q., Weng, H., Wang, J., Zekavat, S. M., Yu, Z., Li, B., Gu, J., Muchnik, S. K., et al. (2019) · Nature Genetics · doi:10.1038/s41588-019-0345-7 · Cited by 407
Genetics of Coronary Artery Disease
McPherson, R., & Tybjærg‐Hansen, A. (2016) · Circulation Research · doi:10.1161/circresaha.115.306566 · Cited by 384
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 ›
Are you an author, or do you see a problem with this page? Request a review
