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γ-Secretase Inhibition Lowers Plasma Triglyceride-Rich Lipoproteins by Stabilizing the LDL Receptor
Open accessAbstract
SUMMARY Excess plasma triglycerides (TG) are a key component of obesity-induced metabolic syndrome. We have shown that γ-secretase inhibitor (GSI) treatment improves glucose tolerance due to inhibition of hepatic Notch signaling, but find additional, Notch-independent reduction of plasma TG-rich lipoproteins (TRLs) in GSI-treated, as well as hepatocyte-specific γ-secretase knockout (L-Ncst) mice, which suggested a primary effect on hepatocyte TRL uptake. Indeed, we found increased VLDL and LDL particle uptake in L-Ncst hepatocytes and Ncst-deficient hepatoma cells, in part through reduced γ-secretase-mediated low-density lipoprotein receptor (LDLR) cleavage and degradation. To exploit this novel finding, we generated a liver-selective Nicastrin ASO, which recapitulated glucose and lipid improvements of L-Ncst mice, with increased levels of hepatocyte LDLR. Collectively, these results identify the role of hepatic γ-secretase to regulate LDLR, and suggest that liver-specific γ-secretase inhibitors may simultaneously improve multiple aspects of the metabolic syndrome.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
Hepatic γ-secretase inhibition lowers plasma triglyceride-rich lipoproteins by stabilizing the LDL receptor, independent of Notch signaling. Nicastrin binds LDLR and promotes γ-secretase-mediated LDLR cleavage and lysosomal degradation, so blocking liver γ-secretase increases LDLR and TRL uptake.
Key findings
- GSI treatment reduced plasma TG, VLDL-TG, and non-HDL cholesterol in chow- or HFD-fed wild-type and L-Rbpj mice, and reduced VLDL-TG more dramatically in obese ob/ob mice, indicating a Notch-independent effect.
- Hepatocyte-specific γ-secretase loss (L-Ncst and tamoxifen-inducible iL-Ncst) and liver-selective Ncst ASO lowered plasma TG and improved glucose tolerance; Ncst ASO achieved >90% Ncst knockdown and did not lower plasma TG in Ldlr−/− or Ldlr ASO-treated mice.
- γ-secretase inhibition increased VLDL/LDL particle uptake in L-Ncst hepatocytes and shNcst McA-RH7777 cells; after 24 hr, only 25% of input ApoC3 remained in medium exposed to shNcst cells versus 60% in shControl cells.
- Nicastrin bound full-length LDLR but not a CTD-deficient mutant; γ-secretase cleavage produced an LDLR CTD and C-terminal fragments, and dCTD-LDLR was unstable and rescued by chloroquine, supporting lysosomal degradation. Alirocumab did not affect plasma TG and showed neither synergy nor competition with Ncst ASO.
Methods
- Mouse models included wild-type C57BL/6, ob/ob, HFD- or chow-fed mice, albumin-Cre;Nicastrinflox/flox (L-Ncst), SA-Cre-ERT2;Nicastrinflox/flox (iL-Ncst), L-Rbpj, and Ldlr−/− mice; primary hepatocytes and McA-RH7777 cells with shControl or shNcst were also used.
- Interventions included dibenzazepine GSI (2 μmol/kg daily for 5 d), Ncst ASO (25 mg/kg weekly for 6 weeks), Ldlr ASO (5 mg/kg), and alirocumab (10 mg/kg s.c. weekly for 3 weeks).
- Analyses included glucose tolerance tests, plasma/hepatic lipid measurements, poloxamer-407 VLDL-TG secretion, olive oil gavage, DiI-VLDL clearance, lipoprotein fractionation, Western blotting, qPCR, cell-surface biotinylation, and VLDL/LDL or human ApoC3-containing particle uptake assays; statistics used t tests or ANOVA with mean ± s.e.m.
Limitations
- The paper states that it cannot rule out indirect, but still LDLR-dependent, mechanisms by which γ-secretase regulates TRL clearance.
- The paper states that how LDLR is differentially regulated by γ-secretase and PCSK9 to affect TRL versus cholesterol uptake is unclear.
- The paper states that all data are from rodent models, so translation to human biology is unknown; the text makes evident that no human clinical validation is provided.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
8 of 16 cited sources checked · 4 supported · 0 flagged · accuracy not yet measured
- Premisecitation
TRLs arising from LPL-mediated lipolysis are cleared by multiple hepatic receptors, including LDLR, LRP1, and syndecan-1 (SDC).
“TRLs arising from LPL-mediated lipolysis are cleared by multiple hepatic receptors, including LDL receptor (LDLR), LDLR-related protein 1 (LRP1), and syndecan-1 (SDC), the predominant hepatic heparin sulfate proteoglycan (HSPG) (Bishop et al., 2008; Foley et al., 2013; MacArthur et al., 2007; Stanford et al., 2009).”
Quote in the paperSubstantial claim2 of 3 sources checked- cites Bishop et al., 2008 source
- cites Foley et al., 2013 source
- cites MacArthur et al., 2007 source
The Introduction describes LPL-generated TRL remnants and discusses LDLR and LRP1 in their clearance. The Discussion establishes a role for hepatic heparan sulfate proteoglycans, but the section ‘HSPGs may act through multiple mechanisms’ only lists syndecan-1 among several liver proteoglycans; it does not identify syndecan-1 as the predominant hepatic HSPG or establish its specific role in TRL clearance. (LLM, conf=0.87)
Experimental — accuracy not yet measured
- Findingown data
Hepatocyte-specific γ-secretase inhibition (L-Ncst mice) lowers plasma TG.
“L-Ncst mice showed both improved glucose tolerance (Figure 2C) as well as lower plasma TG (Figure 2D) as compared to Cre- control mice.”
Quote in the paperSubstantial claim - Findingown data
Transfected LDLR is increased in shNcst cells compared with control cells.
“we found a robust increase in transfected LDLR (with a non-native promoter) in shNcst cells as compared with control cells (Figure 5F and Figure S5E).”
Quote in the paperSubstantial claim - Findingown data
Ncst ASO improves glucose tolerance in chow- or HFD-fed C57BL/6 wild-type mice.
“and improved glucose tolerance (Figure 3D and Figure S3H).”
Quote in the paperNot a substantial claim - Findingown data
L-Ncst livers and shNcst cells show no change in LDLR intracellular trafficking dynamics.
“without apparent change in LDLR intracellular trafficking dynamics (Figure 5C–5E)”
Quote in the paperSubstantial claim
- Findingown data
Ncst ASO does not lower plasma TG in the absence of LDLR.
“although Ncst ASO does not lower plasma TG in the absence of LDLR, these data do not rule-out the possibility that γ-secretase regulates TRL clearance through indirect, but still LDLR-dependent, mechanisms.”
Quote in the paperSubstantial claim - Findingown data
GSI-mediated reduction of VLDL-TG is more dramatic in obese leptin-deficient ob/ob mice.
“GSI-mediated reduction of VLDL-TG was even more dramatic in obese, dyslipidemia-prone (Nishina et al., 1994), leptin-deficient (ob/ob) mice (Figure 1C and 1D).”
Quote in the paperNot a substantial claim - Findingown data
LPL activity in plasma is unchanged in Cre- and L-Ncst mice.
“leading to unchanged LPL activity in plasma of Cre- and L-Ncst mice (Figure S4D).”
Quote in the paperSubstantial claim - Findingown data
L-Ncst livers and shNcst cells show no change in Ldlr mRNA expression with γ-secretase inhibition.
“or Ldlr mRNA expression with γ-secretase inhibition (Figure S5C and S5D).”
Quote in the paperSubstantial claim - Findingown data
Ncst ASO #806498-3 has >90% Ncst knockdown efficiency.
“coupled with >90% Ncst knockdown efficiency.”
Quote in the paperSubstantial claim - Findingown data
L-Ncst mice have no change in VLDL-TG secretion.
“no change in VLDL-TG secretion (Figure 2F)”
Quote in the paperSubstantial claim - Findingown data
L-Ncst mice show reduced TG in VLDL and LDL fractions.
“fractionation of plasma lipoproteins by density gradient ultracentrifugation or size-exclusion fast protein liquid chromatography showed reduced TG in VLDL and LDL fractions in L-Ncst mice (not shown and Figure 2E)”
Quote in the paperSubstantial claim - Findingown data
Less ApoB and ApoC3 remained in media applied to cells lacking γ-secretase.
“Concordantly, less ApoB and ApoC3 remained in media applied to cells lacking γ-secretase (Figure 4F and 4G).”
Quote in the paperSubstantial claim - Findingown data
In presence of epoxomicin, predicted γ-secretase-cleaved LDLR CTD and another C-terminal fragment are observed.
“in the presence of epoxomicin to inhibit proteasomal degradation of LDLR cleavage products, we observed both the predicted γ-secretase-cleaved LDLR cytoplasmic tail domain (CTD), and another C-terminal fragment oft-seen in γ-secretase substrates (Figure 5G).”
Quote in the paperSubstantial claim- Rests on an assumption: The C-terminal fragment observed with epoxomicin is a γ-secretase substrate fragment.
- Findingown data
Administration of a PCSK9 mAb, alirocumab, did not further reduce plasma TG in Ncst ASO-treated mice.
“Consistent with these data, we found that administration of a PCSK9 mAb, alirocumab, did not further reduce plasma TG in Ncst ASO-treated mice.”
Quote in the paperSubstantial claim - Findingown data
Plasma ApoC3 is reduced in GSI-treated, Ncst ASO, L-Ncst and iL-Ncst mice, independent of prandial state.
“we observed reduced plasma ApoC3 in these same mice (Figure 4A and Figure S4E–S4G), independent of the prandial state (Figure S4H).”
Quote in the paperSubstantial claim - Findingown data
ApoC3 appearance in plasma is similar in Poloxamer 407-treated Cre- and L-Ncst mice.
“As ApoC3 appearance in plasma was similar in Poloxamer 407-treated Cre- and L-Ncst mice (Figure 4B)”
Quote in the paperSubstantial claim - Findingown data
LDLR degradation is γ-secretase-dependent, as FL but not dCTD-LDLR accumulated in chloroquine-treated shNcst cells.
“We find that LDLR degradation is γ-secretase-dependent, as FL but not dCTD-LDLR accumulated in chloroquine-treated shNcst cells (Figure 5L).”
Quote in the paperSubstantial claim - Findingown data
γ-secretase inhibition does not change Apoc3, Angptl3 and other apolipoprotein genes or their protein products in livers.
“But we observed unchanged Apoc3, Angptl3 and other apolipoprotein genes, or their protein products, in livers from GSI-treated, Ncst ASO, L-Ncst and iL-Ncst mice (not shown and Figure S4A–S4C)”
Quote in the paperSubstantial claim - Findingown data
GSI treatment does not affect TG secretion.
“we injected mice with Poloxamer-407, which prevents LPL-mediated TG-lipolysis, and found identical TG secretion in control and GSI-treated mice (Figure 1E).”
Quote in the paperSubstantial claim - Findingown data
Pitstop2 negates the differences between controls and cells lacking γ-secretase in ApoB and ApoC3 uptake.
“As predicted, Pitstop2 negated the differences between controls and cells lacking γ-secretase (Figure 5A and 5B and Figure S5A and S5B).”
Quote in the paperSubstantial claim - Findingown data
L-Ncst mice have lower non-HDL cholesterol.
“consistent with lower non-HDL cholesterol in L-Ncst as compared to Cre- control mice (Figure S4I).”
Quote in the paperSubstantial claim - Findingown data
L-Ncst hepatocytes and shNcst McA-RH7777 cells show more intracellular human ApoB and ApoC3 after exposure to purified human VLDL or LDL particles compared to controls.
“we found more intracellular human ApoB and human ApoC3 in L-Ncst hepatocytes (Figure 4D) and shNcst cells (Figure 4E) as compared to the relevant controls.”
Quote in the paperSubstantial claim - Findingown data
After 24hr incubation, only 25% of input ApoC3 remained in medium exposed to shNcst cells, compared to 60% in shControl cells.
“after 24hr incubation, only 25% of input ApoC3 remained in the medium exposed to shNcst cells, as compared to 60% in shControl cells (Figure S4L).”
Quote in the paperSubstantial claim - Findingown data
L-Ncst mice have reduced ApoB and ApoC3 in VLDL fractions.
“we observed a similar reduction in ApoB and ApoC3 in VLDL fractions isolated from L-Ncst mice (Figure 4C)”
Quote in the paperSubstantial claim - Findingown data
L-Ncst mice show improved glucose tolerance.
“L-Ncst mice showed both improved glucose tolerance (Figure 2C) as well as lower plasma TG (Figure 2D) as compared to Cre- control mice.”
Quote in the paperNot a substantial claim - Findingown data
L-Ncst mice have marked reduction in appearance of plasma TG after an oral lipid load.
“a marked reduction in appearance of plasma TG after an oral lipid load (Figure 2G).”
Quote in the paperSubstantial claim - Findingown data
Ncst ASO reduces plasma TG in chow- or HFD-fed C57BL/6 wild-type mice.
“plasma TG (Figure 3C and Figure S3G)”
Quote in the paperSubstantial claim - Findingown data
TG excursion after olive oil gavage is attenuated in GSI-treated mice.
“TG excursion in response to olive oil gavage was attenuate in GSI-treated mice (Figure 1F).”
Quote in the paperSubstantial claim - Interpretationown data
γ-secretase inhibition attenuates multiple metabolic comorbidities of the obese state.
“Nevertheless, these data indicate that γ-secretase inhibition attenuates multiple metabolic comorbidities of the obese state.”
Quote in the paperSubstantial claim - Interpretationown data
Hepatic γ-secretase has a dual role to regulate glucose homeostasis and lipid homeostasis by diverse mechanisms.
“These data support the dual role of hepatic γ-secretase to regulate glucose homeostasis and lipid homeostasis by diverse mechanisms”
Quote in the paperSubstantial claim - Interpretationown data
γ-secretase regulates LDLR turnover, independent of PCSK9.
“These data suggest that γ-secretase regulates LDLR turnover, independent of PCSK9.”
Quote in the paperSubstantial claim - Interpretationown data
GSIs reduce plasma TG by a mechanism independent of known GSI inhibition of hepatocyte Notch.
“Collectively, these results demonstrate that GSIs reduce plasma TG, likely by a mechanism independent of known GSI inhibition of hepatocyte Notch.”
Quote in the paperSubstantial claim - Interpretationown data
γ-secretase has a post-transcriptional effect on LDLR protein stability.
“These data suggest a post-transcriptional effect of γ-secretase on LDLR protein stability.”
Quote in the paperSubstantial claim
- Probably not a substantial claim. 13
- It may state two separate claims as one. 33
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationKnown pathways that regulate post-transcriptional levels of LDLR include PCSK9 and Idol.
“Known pathways that regulate post-transcriptional levels of LDLR include PCSK9 (pro-protein convertase subtilisin/kexin type 9) and Idol (inducible degrader of the LDLR) (Arsenault et al., 2014; Lakoski et al., 2009; Zelcer et al., 2009)”
Quote in the paperNot a substantial claim2 of 3 sources checkedIt may state two separate claims as one.
PremisecitationGSI treatment of diet-induced or genetic mouse models of obesity improved hepatic insulin sensitivity, likely through inhibition of Notch co-activation of FoxO1-mediated hepatic glucose production.
“For instance, we found that GSI treatment of diet-induced or genetic mouse models of obesity improved hepatic insulin sensitivity, likely through inhibition of Notch co-activation of FoxO1-mediated hepatic glucose production (Pajvani et al., 2011).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Pajvani et al., 2011 source
The Results section on γ-secretase inhibitors reports improved glucose levels and tolerance in diet-induced obese and genetically obese ob/ob mice, with findings suggestive of increased hepatic insulin sensitivity. The Discussion describes Notch–FoxO1 cooperation in regulating hepatic glucose production, but the Results and Discussion also state that GSI reduced glucose production in FoxO1-deficient hepatocytes. Thus, the proposed FoxO1-mediated mechanism is not established as the explanation for the GSI effect. (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.
PremisecitationAlirocumab is a PCSK9 monoclonal antibody in clinical use.
“alirocumab, a PCSK9 monoclonal antibody in clinical use (Robinson et al., 2015)”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Robinson et al., 2015 source
The indexed Abstract identifies alirocumab as a monoclonal antibody that inhibits PCSK9 and describes its administration in a clinical trial. It does not establish that alirocumab was in routine clinical use; the repository passages supplied in the prompt do not address that point either. (LLM, conf=0.83)
Experimental — accuracy not yet measured
Probably not a substantial claim.
PremisecitationPCSK9 reroutes internalized LDLR for intracellular degradation.
“As PCSK9 reroutes internalized LDLR for intracellular degradation (Lagace, 2014)”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Lagace, 2014 source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationAn unbiased proteomics screen identified but did not experimentally validate a potential candidate for the γ-secretase effect on hepatocyte TRL uptake, the LDL receptor (LDLR).
“To this end, an unbiased proteomics screen (Hemming et al., 2008) identified but did not experimentally validate a potential candidate for the γ-secretase effect on hepatocyte TRL uptake, the LDL receptor (LDLR).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Hemming et al., 2008 source
The Results section on substrate identification describes an unbiased proteomics screen, but says it identified a protein with a closely related homologue—the LDL receptor (LDLR)—that had previously been identified as a γ-secretase substrate. It does not say the screen identified LDLR itself. The validation section lists the proteins experimentally tested and does not include LDLR; the paper does not examine hepatocyte TRL uptake. (LLM, conf=0.86)
Experimental — accuracy not yet measured
It may state two separate claims as one.
Findingown dataNcst ASO reduces plasma TG in both control and alirocumab-treated mice, with neither synergy nor competition between these inhibitors.
“Ncst ASO reduced plasma TG in both control and alirocumab-treated mice, but we observed neither synergy nor competition between these inhibitors (Figure S6C).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataL-Ncst mice have unchanged body weight, body composition, and liver TG.
“despite unchanged body weight, body composition and liver TG (Figure S2A–S2C), L-Ncst mice showed both improved glucose tolerance (Figure 2C) as well as lower plasma TG (Figure 2D) as compared to Cre- control mice.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataTamoxifen-treated iL-Ncst mice show normal body weight, adiposity, and liver TG.
“tamoxifen-treated iL-Ncst mice showed normal body weight, adiposity and liver TG (Figure S2F–S2H)”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataGenetic or pharmacologic Notch inhibition and constitutively-active Notch1 do not affect plasma TG or cholesterol levels.
“As genetic (hepatocyte-specific deletion of Rbpj; hence L-Rbpj mice (Pajvani et al., 2013)) or more specific pharmacologic Notch inhibition, and conversely, adenoviral transduction of constitutively-active Notch1 did not affect plasma TG or cholesterol levels (Figure S1A–S1D)”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataNcst ASO reduces liver Ncst mRNA and Nicastrin protein levels in chow- or HFD-fed C57BL/6 wild-type mice.
“found reduced liver Ncst mRNA, Nicastrin protein levels (Figure 3A and 3B and Figure S3F)”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataNo difference in hepatic Pcsk9 or Idol expression, and PCSK9 protein levels and secretion with γ-secretase inhibition.
“we observed no difference of hepatic Pcsk9 or Idol expression, and PCSK9 protein levels and secretion with γ-secretase inhibition (Figure S5F–S5K).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataNcst ASO reduces plasma TG and appearance of plasma TG after olive oil gavage in Cre- mice, but not in L-Ncst mice.
“Ncst ASO reduced plasma TG and the appearance of plasma TG after olive oil gavage in Cre-mice, but not in L-Ncst mice (Figure 3E and 3F).”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Findingnone givenSimultaneous inhibition of γ-secretase and PCSK9 appeared to lower both TG and cholesterol.
“Notably, simultaneous inhibition of γ-secretase and PCSK9 appeared to lower both TG and cholesterol, but further work is necessary to test if PCSK9 and γ-secretase have synergistic and additive effects on lipoprotein metabolism in animal models with elevated non-HDL cholesterol (Lagace, 2014).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataNicastrin directly binds full-length LDLR, but not a CTD-deficient LDLR mutant (dCTD).
“we observed that Nicastrin directly binds full-length (FL)-LDLR, but not a CTD-deficient LDLR mutant (dCTD) (Figure 5I) that mimics the structure of LDLR post-γ-secretase cleavage (Figure S5L).”
Quote in the paperSubstantial claim- Rests on an assumption: The dCTD-LDLR mutant mimics the structure of LDLR after γ-secretase cleavage.
It may state two separate claims as one.
Findingown dataTamoxifen-treated iL-Ncst mice show improved glucose tolerance and lower plasma TG.
“but parallel improvements in glucose tolerance (Figure 2H) and plasma TG (Figure 2I) as compared to Cre- mice or vehicle-treated iL-Ncst mice.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown datadCTD-LDLR has lower steady state protein levels, likely due to increased degradation, rescued by chloroquine.
“As predicted, dCTD has lower steady state protein levels, likely accounted for by increased degradation (Figure 5J), rescued by chloroquine treatment to block LDLR lysosomal degradation (Figure 5K).”
Quote in the paperSubstantial claim- Rests on an assumption: The dCTD-LDLR mutant mimics the structure of LDLR after γ-secretase cleavage.
It may state two separate claims as one.
FindingcitationGSI treatment does not change body or adipose weight.
“We did not detect differences in body or adipose weight with GSI treatment (Sparling et al., 2016)”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataDiI-labeled VLDL particles are more rapidly cleared from plasma, with greater hepatic label internalization in L-Ncst than Cre- mice.
“Plasma Dil-VLDL was more rapidly cleared, with concomitantly greater hepatic label internalization in L-Ncst than Cre- mice (Figure 4H and 4I).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataNcst ASO reduces liver Ncst and Psen2 levels in C57BL/6 mice.
“All 4 ASOs, dosed once weekly at 25 mg per kg body weight for 6 weeks, reduced liver Ncst and Psen2 levels as compared to a control ASO composed of the same chemistry and oligonucleotide length (Figure S3B).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataGSI treatment reduces plasma TG, VLDL-TG, and non-HDL cholesterol in normal chow- or HFD-fed wild-type and L-Rbpj mice.
“GSI treatment of normal chow- or high fat diet (HFD)-fed wild-type and L-Rbpj mice led to a significant reduction in plasma TG, VLDL-TG, and non-HDL cholesterol (Figure 1A, 1B and S1E).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataNcst ASO reduces plasma TG in both Cre- and L-Rbpj mice, consistent with a Notch-independent effect.
“Ncst ASO reduced plasma TG in both Cre- and L-Rbpj mice, consistent with a Notch-independent effect (Figure S3N).”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
FindingcitationAlirocumab reduces plasma cholesterol levels but has no effect on plasma TG.
“As expected (Berger et al., 2017), alirocumab reduced plasma cholesterol levels (Figure S6B), but had no effect on plasma TG.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataNcst ASO decreases plasma TG and ApoC3, and plasma TG excursion after olive oil gavage, but not in Ldlr−/− or Ldlr ASO-treated mice.
“Consistent with earlier results, Ncst ASO decreased plasma TG and ApoC3 (Figure 6C, 6D and S6D), as well as plasma TG excursion after olive oil gavage, but not in Ldlr−/− or concomitantly-treated Ldlr ASO mice (Figure 6E and 6F).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataLDLR lacking its short CTD is inherently unstable and undergoes lysosomal degradation.
“Nonetheless, our results show that LDLR lacking its short CTD, which represents the end-product of γ-secretase activity, is inherently unstable and undergoes lysosomal degradation.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataWith GSI treatment, LDLR CTD levels are reduced with parallel C-terminal fragment accumulation, confirming γ-secretase-dependent LDLR cleavage.
“With GSI treatment, however, LDLR CTD levels were reduced with parallel C-terminal fragment accumulation (Figure 5H), confirming our hypothesis of γ-secretase-dependent LDLR cleavage.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataApoC3 disappearance from plasma is accelerated with hepatic γ-secretase inhibition, suggestive of enhanced uptake of VLDL/LDL particles.
“these data suggested that ApoC3 disappearance from plasma was accelerated with hepatic γ-secretase inhibition, suggestive of enhanced uptake of VLDL/LDL particles.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationnone givenAll data presented is derived from rodent models, and translation to human biology is unknown.
“Finally, as all data presented is derived from rodent models, translation to human biology is unknown”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Interpretationown dataNicastrin binds LDLR, allowing γ-secretase-mediated intramembrane proteolysis, releasing the short LDLR CTD and rendering LDLR susceptible to lysosomal degradation.
“In sum, these data support the conclusion that Nicastrin binds LDLR, allowing γ-secretase-mediated intramembrane proteolysis, releasing the short LDLR CTD (which is quickly degraded by the proteasome) and rendering LDLR susceptible to lysosomal degradation.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
PremisecitationPCSK9 loss-of-function or pharmacologic inhibition lowers LDL cholesterol, but effects on plasma TG in treated patients are less robust and reproducible.
“PCSK9 loss-of-function or pharmacologic inhibition lowers LDL cholesterol, but effects on plasma TG in treated patients are less robust and reproducible (Everett et al., 2015).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Everett et al., 2015 source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationHypertriglyceridemia is often not effectively treated, leading to a significant unmet therapeutic need.
“Unfortunately, hypertriglyceridemia is often not effectively treated, leading to a significant unmet therapeutic need in an increasingly obese population (Brunzell and Ayyobi, 2003).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Brunzell and Ayyobi, 2003 source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown dataIn L-Ncst, iL-Ncst and Ncst ASO-treated mice, 6-7 mice per group were calculated to be needed to detect a 25% difference in plasma TG with a power of 0.8 and p<0.05, based on preliminary data from GSI-treated mice.
“Based on preliminary data from GSI-treated mice, we calculated that 6–7 mice/group would be needed to detect a 25% difference in plasma TG in L-Ncst, iL-Ncst and Ncst ASO-treated mice, with a power of 0.8 and p<0.05.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Interpretationown dataTreatment with GSIs or liver-specific γ-secretase inhibition recapitulates insulin-sensitizing effects of loss of hepatocyte Notch signaling, but reduces plasma TG and non-HDL cholesterol in a Notch-independent manner.
“Our data show that treatment with GSIs, or more specific approaches to blocking liver γ-secretase activity (Ncst ASO; L-Ncst or iL-Ncst mice), recapitulates the insulin-sensitizing effects of loss of hepatocyte Notch signaling, but simultaneously reduces plasma TG and non-HDL cholesterol in a Notch-independent manner.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Premisecitationγ-secretase is a multiprotein complex consisting of redundant catalytic and regulatory subunits, as well as unique targeting (Nicastrin) and enhancer (PEN2) components that regulate intramembrane proteolysis of Type 1 transmembrane proteins.
“The γ-secretase is a multiprotein complex consisting of redundant catalytic (Presenilin 1 or 2) and regulatory (Aph-1a or -1b) subunits, as well as unique targeting (Nicastrin) and enhancer (PEN2) components that regulate intramembrane proteolysis of Type 1 transmembrane proteins (Wolfe, 2006).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Wolfe, 2006 source
It may state two separate claims as one.
Interpretationown dataγ-secretase inhibition increases cellular uptake of TRLs, to reduce plasma TG and non-HDL cholesterol.
“These data show that γ-secretase inhibition increases cellular uptake of TRLs, to reduce plasma TG and non-HDL cholesterol.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenImmunoblots were conducted on 3-5 samples randomly chosen within each experimental cohort.
“Immunoblots were conducted on 3–5 samples randomly chosen within each experimental cohort”
Quote in the paperNot a substantial claimProbably not a substantial claim.
PremisecitationBoth LDLR and LRP1 have been reported as putative γ-secretase targets.
“As both LDLR and LRP1 have been reported as putative γ-secretase targets (Hemming et al., 2008)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Hemming et al., 2008 source
Checked before — its earlier verdict is held back until a new check runs.
It may state two separate claims as one.
Interpretationown dataNicastrin directly targets LDLR for γ-secretase-mediated proteolysis, which renders LDLR susceptible to lysosomal degradation, and decreases uptake of TG-rich VLDL/LDL particles.
“Our data show that Nicastrin directly targets LDLR for γ-secretase-mediated proteolysis as predicted by a prior proteomics screen (Hemming et al., 2008), which in turn renders LDLR susceptible to lysosomal degradation, and decreases uptake of TG-rich VLDL/LDL particles (Gordts et al., 2016) but we cannot rule out indirect mechanisms that may contribute to TRL clearance.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataOur work demonstrates the novel role of hepatic γ-secretase to regulate LDLR, which in turn contributes to enhanced clearance of TRLs.
“Our work demonstrates the novel role of hepatic γ-secretase to regulate LDLR, which in turn contributes to enhanced clearance of TRLs.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
InterpretationreasoningIncreased baseline hepatocyte plasma membrane LDLR, by dint of γ-secretase inhibition, allows rapid binding and uptake of TRLs, which may distinguish this approach from PCSK9 antagonism.
“We postulate that increased “baseline” hepatocyte plasma membrane LDLR, by dint of γ-secretase inhibition, allows rapid binding and uptake of TRLs, which may distinguish this approach from PCSK9 antagonism that preferentially increases LDLR recycling.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataγ-secretase destabilizes LDLR, and inhibition of hepatic γ-secretase activity increases hepatic LDLR to facilitate increased TRL uptake and lower plasma TG.
“Collectively, these experiments show that the γ-secretase destabilizes LDLR, and that inhibition of hepatic γ-secretase activity increases hepatic LDLR to facilitate increased TRL uptake and lower plasma TG.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationHypertriglyceridemia is an independent risk factor for coronary heart disease above and beyond other insulin resistance-related complications.
“One of the core components of the metabolic syndrome is excess plasma triglycerides (TG), or hypertriglyceridemia, which is an independent risk factor for coronary heart disease (CHD), above and beyond other insulin resistance-related complications (i.e., high apolipoprotein B (ApoB), low high-density lipoprotein (HDL) cholesterol levels, hypertension and Type 2 Diabetes) (Brunzell, 2007; Nordestg”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Study design and conductnone givenNo animals or data were excluded from any analysis; all mice studied were included in subsequent analysis.
“All mice studied were included in subsequent analysis.”
- Also stated in: § METHODS DETAILS · plain
“No animals or data was excluded from any analysis.”
Quote in the paperNot a substantial claim- Also stated in: § METHODS DETAILS · plain
The paper relies on this without support.
The dCTD-LDLR mutant mimics the structure of LDLR after γ-secretase cleavage.
“a CTD-deficient LDLR mutant (dCTD) (Figure 5I) that mimics the structure of LDLR post-γ-secretase cleavage (Figure S5L).”
The paper relies on this without support.
The C-terminal fragment observed with epoxomicin is a γ-secretase substrate fragment.
“another C-terminal fragment oft-seen in γ-secretase substrates (Figure 5G).”
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?
Changes in LDLR transcription, internalization, stability, subcellular localization, and degradation all affect the concentration of LDL-c in blood.
“Its central role in this process is illustrated by the notion that changes in its transcription, 22 internalization, 23,24 stability, 25 subcellular localization, and degradation 26,27 all affect the concentration of LDL-c in blood.”
From A common variant in CCDC93 protects against myocardial infarction and cardiovascular mortality by regulating endosomal trafficking of low-density lipoprotein receptor (2020) · cites this paper as [25]
Citation 25 is attached to LDLR stability, not to the sentence’s other listed mechanisms. The Results section, “γ-secretase regulates LDLR protein stability,” shows that γ-secretase inhibition stabilizes LDLR, but the paper primarily links this pathway to clearance of triglyceride-rich lipoproteins; it does not establish that this change in stability alters blood LDL-c. The Discussion separately notes that PCSK9 inhibition lowers LDL cholesterol. (LLM, conf=0.82)
Experimental — accuracy not yet measuredγ-secretase promotes ectodomain shedding of LDLR, decreasing LDLR.
“γ-secretase Promotes ectodomain shedding of LDLR ↓ [110-112, 114]”
From The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms (2025) · cites this paper as [114]
The Results section (“γ-secretase regulates LDLR protein stability”) reports that γ-secretase-mediated cleavage destabilizes LDLR and promotes its lysosomal degradation. But the Discussion describes this as intramembrane proteolysis and says LDLR may be shed by other secretases before γ-secretase cleavage; it does not establish that γ-secretase promotes ectodomain shedding. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe lack of its cytosolic domain destabilises the LDLR and targets what is left of the receptor to the lysosome for degradation.
“The lack of its cytosolic domain destabilises the LDLR and targets what is left of the receptor to the lysosome for degradation [52].”
From Post-translational regulation of the low-density lipoprotein receptor provides new targets for cholesterol regulation (2024) · cites this paper as [52]
The released intracellular cytosolic domain of LDLR is degraded by the proteasome.
“The released intracellular cytosolic domain of LDLR is degraded by the proteasome (Figure 1G).”
From Post-translational regulation of the low-density lipoprotein receptor provides new targets for cholesterol regulation (2024) · cites this paper as [52]
Targeted lysosomal degradation of the LDLR in hepatocytes has been observed following proteolytic cleavage of the receptor by γ-secretase.
“Targeted lysosomal degradation of the LDLR in hepatocytes has also been observed following proteolytic cleavage of the receptor by γ-secretase [52] (Figure 1G).”
From Post-translational regulation of the low-density lipoprotein receptor provides new targets for cholesterol regulation (2024) · cites this paper as [52]
Proteolytic cleavage of the LDLR transmembrane region by γ-secretase destabilises the receptor and directs it to the lysosome for degradation.
“Proteolytic cleavage of the transmembrane region of the LDLR by γ-secretase destabilises the receptor, directing it to the lysosome for degradation.”
From Post-translational regulation of the low-density lipoprotein receptor provides new targets for cholesterol regulation (2024) · cites this paper as [52]
ASOs targeting Nicastrin resulted in a similar outcome to GSI treatment.
“This resulted in a similar outcome, and demonstrated that LDL clearance by hepatocytes was increased as a result of elevated total and cell-surface abundance of the LDLR.”
From The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms (2025) · cites this paper as [114]
GSIs have revealed unexpected benefits in lipid metabolism.
“However, they have revealed unexpected benefits in lipid metabolism [114].”
From The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms (2025) · cites this paper as [114]
The increase in hepatic LDLR upon Nicastrin absence is attributed to the absence of Nicastrin-mediated binding to the C-terminal of the LDLR and the lack of subsequent cleavage of the receptor.
“The increase in hepatic LDLR was attributed to absence of Nicastrin-mediated binding to the C-terminal of the LDLR, and the lack of subsequent cleavage of the receptor [114].”
From The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms (2025) · cites this paper as [114]
In mice, treatment with GSIs reduced plasma triglycerides, VLDL-TG, and non-HDL cholesterol.
“Specifically, mice treated with GSIs showed reduced plasma triglycerides, VLDL-TG, and non-HDL cholesterol.”
From The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms (2025) · cites this paper as [114]
γ-secretase has been shown to cleave full-length LDLR, although extracellular cleavage may still occur prior to γ-secretase cleavage.
“However, γ-secretase has been shown to cleave the full-length LDLR, although extracellular cleavage may still occur prior to γ-secretase cleavage104.”
From Pathways and Molecular Mechanisms Governing LDL Receptor Regulation (2025) · cites this paper as [104]
γ-secretase-mediated cleavage of the LDLR occurs on the uncleaved full-length receptor.
“However, γ-secretase-mediated cleavage of the LDLR has been shown to occur on the uncleaved full-length receptor, although there is the possibility that the receptor may be cleaved extracellularly prior to γ-secretase cleavage [52]”
From Post-translational regulation of the low-density lipoprotein receptor provides new targets for cholesterol regulation (2024) · cites this paper as [52]
The nicastrin subunit of γ-secretase binds to the LDLR and recruits the rest of the γ-secretase complex, resulting in cleavage of the LDLR.
“The nicastrin subunit of γ-secretase binds to the LDLR and recruits the rest of the γ-secretase complex, resulting in the cleavage of the LDLR”
From Post-translational regulation of the low-density lipoprotein receptor provides new targets for cholesterol regulation (2024) · cites this paper as [52]
ASOs targeting Nicastrin increased LDL clearance by hepatocytes as a result of elevated total and cell-surface abundance of the LDLR.
“This resulted in a similar outcome, and demonstrated that LDL clearance by hepatocytes was increased as a result of elevated total and cell-surface abundance of the LDLR.”
From The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms (2025) · cites this paper as [114]
Inhibition of γ-secretase primarily improves plasma triglycerides as opposed to plasma cholesterol.
“Though this enzyme directly cleaves the LDLR, inhibition of γ-secretase primarily improves plasma triglycerides as opposed to plasma cholesterol105.”
From Pathways and Molecular Mechanisms Governing LDL Receptor Regulation (2025) · cites this paper as [105]
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Bishop, J. R., Stanford, K. I., & Esko, J. D. (2008) · Current Opinion in Lipidology · doi:10.1097/mol.0b013e3282feec2d · Cited by 49
Lee, Y.-H., Yun, M. R., Kim, H. M., Jeon, B. H., Park, B.-C., Lee, B.-W., Kang, E. S., Lee, H. C., Park, Y. W., & Cha, B.-S. (2015) · International Journal of Obesity · doi:10.1038/ijo.2015.173 · Cited by 40
PCSK9-mediated degradation of the LDL receptor generates a 17 kDa C-terminal LDL receptor fragment
Tveten, K., Str⊘m, T. B., Berge, K. E., & Leren, T. P. (2013) · Journal of Lipid Research · doi:10.1194/jlr.m034371 · Cited by 39
Altenburg, M. K., Arbonés-Mainar, J. M., Johnson, L. A., Wilder, J., & Maeda, N. (2008) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.108.164863 · Cited by 38
Johnson, L. A., Arbonés-Mainar, J. M., Fox, R. G., Pendse, A. A., Altenburg, M. K., Kim, H., & Maeda, N. (2011) · Diabetes · doi:10.2337/db11-0466 · Cited by 34
Sparling, D. P., Yu, J., Kim, K., Zhu, C., Brachs, S., Birkenfeld, A. L., & Pajvani, U. B. (2015) · Molecular Metabolism · doi:10.1016/j.molmet.2015.11.006 · Cited by 24
Self-citationMorphologic and Functional Effects of Gamma Secretase Inhibition on Splenic Marginal Zone B Cells
de Vera Mudry, M. C., Regenass-Lechner, F., Ozmen, L., Altmann, B., Festag, M., Singer, T., Müller, L., Jacobsen, H., & Flohr, A. (2012) · International Journal of Alzheimer's Disease · doi:10.1155/2012/289412 · Cited by 6
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1 of the 80 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Hepatocyte Notch activation induces liver fibrosis in nonalcoholic steatohepatitis
Zhu, C., Kim, K., Wang, X., Bartolome, A., Salomao, M., Dongiovanni, P., Meroni, M., Graham, M. J., Yates, K. P., Diehl, A. M., et al. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aat0344 · Cited by 250
Self-citationMaladaptive regeneration - the reawakening of developmental pathways in NASH and fibrosis
Zhu, C., Tabas, I., Schwabe, R. F., & Pajvani, U. B. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-020-00365-6 · Cited by 112
Self-citationZanoni, P., Velagapudi, S., Yalçınkaya, M., Rohrer, L., & von Eckardstein, A. (2018) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2018.06.881 · Cited by 98
Regulation and function of insulin and insulin-like growth factor receptor signalling
Choi, E., Duan, C., & Bai, X. (2025) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-025-00826-3 · Cited by 97
Fang, Z., Ruan, B., Liu, J., Duan, J., Yue, Z., Song, P., Xu, H., Ding, J., Xu, C., Dou, G., et al. (2022) · Hepatology · doi:10.1002/hep.32332 · Cited by 91
Functions of amyloid precursor protein in metabolic diseases
Guo, Y., Wang, Q., Chen, S., & Xu, C. (2020) · Metabolism · doi:10.1016/j.metabol.2020.154454 · Cited by 87
Notch signaling dynamically regulates adult β cell proliferation and maturity
Bartolomé, A., Zhu, C., Sussel, L., & Pajvani, U. B. (2018) · Journal of Clinical Investigation · doi:10.1172/jci98098 · Cited by 67
Self-citationAdipocyte PHLPP2 inhibition prevents obesity-induced fatty liver
Kim, K., Kang, J. K., Jung, Y. H., Lee, S. B., Rametta, R., Dongiovanni, P., Valenti, L. V. C., & Pajvani, U. B. (2021) · Nature Communications · doi:10.1038/s41467-021-22106-2 · Cited by 48
Self-citationThe role of lysosomal membrane proteins in glucose and lipid metabolism
Gu, J., Geng, M., Qi, M., Wang, L., Zhang, Y., & Gao, J. (2021) · The FASEB Journal · doi:10.1096/fj.202002602r · Cited by 40
Pathways and Molecular Mechanisms Governing LDL Receptor Regulation
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Poteser, M., Hutter, H., Moshammer, H. M., & Weitensfelder, L. (2020) · International Journal of Hygiene and Environmental Health · doi:10.1016/j.ijheh.2020.113566 · Cited by 32
Rimbert, A., Dalila, N., Wolters, J. C., Huijkman, N., Smit, M., Kloosterhuis, N., Riemsma, M., van der Veen, Y., Singla, A., van Dijk, F., et al. (2020) · European Heart Journal · doi:10.1093/eurheartj/ehz727 · Cited by 24
Molecular Regulation and Therapeutic Targeting of VLDL Production in Cardiometabolic Disease
Burks, K. H., Stitziel, N. O., & Davidson, N. O. (2024) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2024.101409 · Cited by 24
Antisense oligonucleotide is a promising intervention for liver diseases
Lu, K., Fan, Q., & Zou, X. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.1061842 · Cited by 20
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Self-citationThe low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms
Ndoj, K., Meurs, A., Papaioannou, D., Bjune, K., & Zelcer, N. (2025) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2024.119082 · Cited by 17
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The manipulator behind “Scissors”: γ -secretase and its modulators in Alzheimer’s disease
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IDOL Deficiency Inhibits Cholesterol-Rich Diet–Induced Atherosclerosis in Rabbits
Koike, T., Koike, Y., Niimi, M., Guo, Y., Yang, D., Song, J. W., Xu, J., Tang, X., Ren, Z., Kong, X., et al. (2025) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.125.322417 · Cited by 3
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Self-citationThe γ-secretase complex: from discovery to a therapeutic target
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Self-citation
Metadata
- Authors
- Kim, K., Goldberg, I. J., Graham, M. J., Sundaram, M., Bertaggia, E., Lee, S. X., Qiang, L., Haeusler, R. A., Metzger, D., Chambon, P., Yao, Z., Ginsberg, H. N., & Pajvani, U. B.
- Affiliations
- Columbia University (US)
- New York University (US)
- Ionis Pharmaceuticals (United States) (US)
- University of Ottawa (CA)
- Institut de génétique et de biologie moléculaire et cellulaire (FR)
- Columbia University Irving Medical Center (US)
- Corresponding author
- Pajvani, Utpal B.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2018-04
- Volume
- 27
- Issue
- 4
- Pages
- 816-827.e4
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC5884729
- OpenAlex
- W2789393273
- Semantic Scholar
- 6175989fac3cd3d92d868c80adfc2164a7b90aa1
- Cited by
- 26
- References
- 80
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 3 · 2022: 3 · 2021: 3 · 2020: 6 · 2019: 2 · 2018: 3
- FWCI
- 1.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- Funders
- NIH (DK103818, HL46095, HL92969, HL125649)
- Edward Mallinckrodt, Jr., Foundation Grant
- Paul Marks Scholarship
- Canadian Institutes of Health Research (MOP 123279)
- AHA Scientist Development Grant (17SDG33660031)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Keywords
- gamma-secretase inhibition, LDL receptor, triglyceride-rich lipoproteins, nicastrin, LDL uptake, hepatocytes, metabolic syndrome, obesity, glucose tolerance, antisense oligonucleotides, lipoprotein metabolism
- MeSH terms
- Animals, Cells, Cultured, Disease Models, Animal, Glucose, Lipoproteins, Cholesterol, LDL, Liver, Male, Mice, Inbred C57BL, Receptors, LDL, Triglycerides, Cholesterol, VLDL, Glucose Intolerance, Hepatocytes, Metabolic Syndrome, Lipid Metabolism, Mice, Amyloid Precursor Protein Secretases
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 2026-11-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-11-09 (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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