The DOI matches its Crossref record; 25 of the 25 references it cites were found in a registry or an index; 21 of the 27 sources its claims cite were checked for support.
The Sirt1 activator SRT3025 provides atheroprotection in Apoe−/− mice by reducing hepatic Pcsk9 secretion and enhancing Ldlr expression
Open accessAbstract
AIMS: The deacetylase sirtuin 1 (Sirt1) exerts beneficial effects on lipid metabolism, but its roles in plasma LDL-cholesterol regulation and atherosclerosis are controversial. Thus, we applied the pharmacological Sirt1 activator SRT3025 in a mouse model of atherosclerosis and in hepatocyte culture. METHODS AND RESULTS: Apolipoprotein E-deficient (Apoe(-/-)) mice were fed a high-cholesterol diet (1.25% w/w) supplemented with SRT3025 (3.18 g kg(-1) diet) for 12 weeks. In vitro, the drug activated wild-type Sirt1 protein, but not the activation-resistant Sirt1 mutant; in vivo, it increased deacetylation of hepatic p65 and skeletal muscle Foxo1. SRT3025 treatment decreased plasma levels of LDL-cholesterol and total cholesterol and reduced atherosclerosis. Drug treatment did not change mRNA expression of hepatic LDL receptor (Ldlr) and proprotein convertase subtilisin/kexin type 9 (Pcsk9), but increased their protein expression indicating post-translational effects. Consistent with hepatocyte Ldlr and Pcsk9 accumulation, we found reduced plasma levels of Pcsk9 after pharmacological Sirt1 activation. In vitro administration of SRT3025 to cultured AML12 hepatocytes attenuated Pcsk9 secretion and its binding to Ldlr, thereby reducing Pcsk9-mediated Ldlr degradation and increasing Ldlr expression and LDL uptake. Co-administration of exogenous Pcsk9 with SRT3025 blunted these effects. Sirt1 activation with SRT3025 in Ldlr(-/-) mice reduced neither plasma Pcsk9, nor LDL-cholesterol levels, nor atherosclerosis. CONCLUSION: We identify reduction in Pcsk9 secretion as a novel effect of Sirt1 activity and uncover Ldlr as a prerequisite for Sirt1-mediated atheroprotection in mice. Pharmacological activation of Sirt1 appears promising to be tested in patients for its effects on plasma Pcsk9, LDL-cholesterol, and atherosclerosis.
Overview
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Written from the paper’s full text.
TL;DR
Pharmacological Sirt1 activation with SRT3025 in Apoe−/− mice reduced hepatic Pcsk9 secretion, increased hepatic Ldlr protein, lowered plasma LDL-cholesterol, and reduced atherosclerosis; these effects required Ldlr and were absent in Ldlr−/− mice. The study identifies reduced Pcsk9 secretion as a novel Sirt1 effect and supports testing Sirt1 activators for plasma Pcsk9, LDL-cholesterol, and atherosclerosis in patients.
Key findings
- In Apoe−/− mice fed a high-cholesterol diet, SRT3025 (3.18 g kg−1 diet for 12 weeks, n = 9 vs placebo n = 9) reduced plaque size in thoraco-abdominal aortae en face and aortic roots, reduced plaque Cd68-positive macrophages and Vcam-1 expression, and significantly lowered plasma total-, LDL-, and VLDL-cholesterol; triglycerides and HDL-cholesterol were unchanged. Plasma Mcp-1 and Il-6 were also reduced.
- SRT3025 concentration-dependently activated wild-type Sirt1 but not the activation-resistant Sirt1 mutant E230K in vitro, and increased deacetylation of hepatic p65 and skeletal muscle Foxo1 in vivo. It also prevented weight gain and epididymal white adipose tissue increase without affecting food intake.
- In Apoe−/− liver, SRT3025 did not change Ldlr or Pcsk9 mRNA but increased both proteins, and reduced plasma Pcsk9. In AML12 hepatocytes, 10 μM SRT3025 increased Ldlr and Pcsk9 protein, decreased Pcsk9 secretion, impaired Pcsk9 binding to Ldlr, and increased LDL uptake; exogenous active Pcsk9 (3 ng ml−1) blunted the SRT3025-induced increase in Ldlr protein and LDL uptake. Sirt1 knockdown prevented and Sirt1 overexpression mimicked the Ldlr increase.
- In Ldlr−/− mice, SRT3025 did not reduce atherosclerosis, plasma Pcsk9, or LDL-cholesterol; total and VLDL-cholesterol increased. Baseline plasma Pcsk9 was about 20-fold higher in Ldlr−/− than Apoe−/− mice, and SRT3025 caused a minimal but significant increase in plasma Pcsk9 in Ldlr−/− mice, while inflammation was still reduced.
Methods
- Male Apoe−/− or Ldlr−/− mice on a pure C57BL/6J background were fed a high-cholesterol diet (1.25% w/w) supplemented with or without SRT3025 (3.18 g kg−1 diet) for 12 weeks starting at 8 weeks of age; n = 9 per group. Mice were sacrificed after overnight fasting, and EDTA blood and tissues were harvested.
- AML12 mouse hepatoma cells were cultured and treated with 10 μM SRT3025 in 1% DMSO where indicated. Experiments included Sirt1 knockdown and overexpression, co-immunoprecipitation of Pcsk9 and Ldlr, BODIPY-labelled LDL uptake, Western blots, and mRNA expression analyses.
- Atherosclerosis was assessed by en face thoraco-abdominal aortae and aortic root cross-sections stained with oil-red O or immunohistochemically for Cd68 or Vcam-1; plasma cholesterol distribution was measured by gel filtration chromatography. Statistics used means ± SD, Kolmogorov–Smirnov test, unpaired two-tailed Student’s t-test or Mann–Whitney test, and Kruskal–Wallis with Dunn’s post-hoc comparison; significance was P < 0.05, with at least three independent experiments in triplicates.
Limitations
- The paper states that the mechanisms by which Sirt1 affects Pcsk9 secretion remain to be investigated, and that future studies are needed to translate the effects of pharmacological Sirt1 activation to patients. It also notes that specific investigation of Pcsk9-dependent alterations on atherosclerosis may be hampered by reciprocal changes in Ldlr.
- Evident from the text: findings are limited to male mouse models on a high-cholesterol diet and to AML12 hepatoma cells in vitro, with no human clinical outcomes reported. SRT3025 was provided by Sirtris/GSK, and several authors report conflicts of interest, though this is not framed as a study limitation.
Model-written summary. Check it against the paper before relying on it.
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Verification
Claims the paper makes
21 of 27 cited sources checked · 13 supported · 1 flagged · accuracy not yet measured
- Interpretationown data
SRT3025 acts by allosteric binding to Sirt1 at the lysine site 230, which is located at its catalytic core.
“Thus, similar to previously described Sirt1 activators,15 SRT3025 acts by allosteric binding to Sirt1 at the lysine site 230, which is located at its catalytic core.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [15] Hubbard, 2013, Evidence for a common mechanism of SIRT1 regulation by allosteric activators, Science source
The paper supports allosteric activation of SIRT1 by previously described activators, but it identifies residue 230 as glutamate (Glu230), not lysine, and places it immediately N-terminal to the catalytic core, not within it (Abstract section; page unavailable). It reports that replacing Glu230 with lysine attenuated activation. Our copy does not mention SRT3025, so it cannot establish that compound’s binding site. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured
- Premisecitation
Ldlr is the main route of Pcsk9 clearance.
“Ldlr was reported to be the main route of Pcsk9 clearance.22”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [22] Tavori, 2013, Serum proprotein convertase subtilisin/kexin type 9 and cell surface low-density lipoprotein receptor: evidence for a reciprocal regulation, Circulation source
- Premisecitation
Sirt1 has been shown to be atheroprotective in Apoe−/− mice.
“Sirt1 has been shown to be atheroprotective in apolipoprotein E-deficient (Apoe−/−) mice2–4 whereas genetic overexpression of Sirt1 in LDL-receptor-deficient (Ldlr−/−) mice enhanced atherosclerosis.5”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [2] Zhang, 2008, Endothelium-specific overexpression of class III deacetylase SIRT1 decreases atherosclerosis in apolipoprotein E-deficient mice, Cardiovasc Res source
- cites [3] Stein, 2010, SIRT1 decreases Lox-1-mediated foam cell formation in atherogenesis, Eur Heart J source
- cites [4] Gorenne, 2013, Vascular smooth muscle cell sirtuin 1 protects against DNA damage and inhibits atherosclerosis, Circulation source
- Premisecitation
Administration of a Sirt1 activating drug to elderly volunteers and cigarette smokers decreased plasma levels of total and LDL-cholesterol.
“Conversely, administration of a Sirt1 activating drug to elderly volunteers and cigarette smokers decreased plasma levels of total and LDL-cholesterol.8,9”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [8] Libri, 2012, A pilot randomized, placebo controlled, double blind phase I trial of the novel SIRT1 activator SRT2104 in elderly volunteers, PLoS One source
The Results (Exploratory Pharmacodynamic Measures; page unavailable) report decreased total and LDL cholesterol after SRT2104 treatment in elderly volunteers. The Methods (Study Participants, Design and Treatment; page unavailable) explicitly exclude users of tobacco or nicotine products, so this paper does not support the claim about cigarette smokers. (LLM, conf=0.90)
Experimental — accuracy not yet measured - cites [9] Venkatasubramanian, 2013, Cardiovascular effects of a novel SIRT1 activator, SRT2104, in otherwise healthy cigarette smokers, J Am Heart Assoc source
- Premisecitation
Ldlr plays a critical role in the regulation of plasma LDL-cholesterol levels.
“Ldlr plays a critical role in the regulation of plasma LDL-cholesterol levels,10,11 a key determinant of atherogenesis.17”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [10] Dietschy, 1984, Regulation of low density lipoprotein uptake and degradation in different animals species, Agents Actions Suppl source
- cites [11] Osono, 1995, Role of the low density lipoprotein receptor in the flux of cholesterol through the plasma and across the tissues of the mouse, J Clin Invest source
- Premisecitation
Hepatic deletion of Sirt1 in C57BL/6 mice fed a high-cholesterol diet induced mild hypercholesterolemia.
“Hepatic deletion of Sirt1 in C57BL/6 mice fed a high-cholesterol diet induced mild hypercholesterolemia.7”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [7] Purushotham, 2009, Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation, Cell Metab source
The Animal experiments section describes liver-specific SIRT1 knockout mice on a C57BL/6 background, and the Results describe feeding them a western diet containing cholesterol. The Results and Discussion report increased cholesterol in the liver, but do not establish the claimed mild hypercholesterolemia (elevated blood cholesterol). No page numbers are available in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measured
- Premisecitation
Hepatic Ldlr clears LDL-cholesterol from the blood stream.
“Hepatic Ldlr clears LDL-cholesterol from the blood stream.10,11”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [10] Dietschy, 1984, Regulation of low density lipoprotein uptake and degradation in different animals species, Agents Actions Suppl source
- cites [11] Osono, 1995, Role of the low density lipoprotein receptor in the flux of cholesterol through the plasma and across the tissues of the mouse, J Clin Invest source
- Premisecitation
Ldlr turnover depends on Pcsk9.
“Transcription of Ldlr is controlled by the sterol-responsive element binding protein 2 (Srebp2),12 while its turnover depends on proprotein convertase subtilisin/kexin type 9 (Pcsk9), a serine protease.13”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [13] Attie, 2005, Dual regulation of the LDL receptor—some clarity and new questions, Cell Metab source
- Premisecitation
Constitutive Sirt1 overexpression in Ldlr−/− mice was associated with increased atherosclerosis.
“Furthermore, constitutive Sirt1 overexpression in Ldlr−/− mice was associated with increased atherosclerosis.5”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [5] Qiang, 2011, Proatherogenic abnormalities of lipid metabolism in SirT1 transgenic mice are mediated through Creb deacetylation, Cell Metab source
- Premisecitation
Sirt1 regulates plasma LDL-cholesterol.
“These studies suggest that Sirt1 regulates plasma LDL-cholesterol.”
Quote in the paperSubstantial claim3 of 3 sources checked- cites [7] Purushotham, 2009, Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation, Cell Metab source
The Results section reports higher liver cholesterol in SIRT1-deficient mice, and the Discussion describes altered hepatic cholesterol metabolism. Those passages support a role for SIRT1 in cholesterol metabolism, but they do not establish regulation of plasma LDL-cholesterol; the Methods mention measuring serum cholesterol, not LDL-cholesterol specifically. Page numbers are unavailable in our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measured - cites [8] Libri, 2012, A pilot randomized, placebo controlled, double blind phase I trial of the novel SIRT1 activator SRT2104 in elderly volunteers, PLoS One source
- cites [9] Venkatasubramanian, 2013, Cardiovascular effects of a novel SIRT1 activator, SRT2104, in otherwise healthy cigarette smokers, J Am Heart Assoc source
- Premisecitation
Statin therapy increases hepatic Ldlr and plasma Pcsk9 activity, limiting its effect on LDL-cholesterol.
“Of note, statin therapy not only increases hepatic Ldlr, but also plasma Pcsk9 activity, thus limiting its effect on LDL-cholesterol.23”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [23] Welder, 2010, High-dose atorvastatin causes a rapid sustained increase in human serum PCSK9 and disrupts its correlation with LDL cholesterol, J Lipid Res source
The Discussion says statins increase LDLR and PCSK9 gene expression, and reports increased circulating PCSK9 protein after atorvastatin treatment. It proposes that increased PCSK9 may explain the limited additional LDL-C lowering from higher statin doses, but explicitly calls that explanation unproven. The study measures PCSK9 protein levels, not plasma PCSK9 activity. (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Premisecitation
Pcsk9 targets Ldlr for lysosomal degradation rather than for recycling to the cell surface.
“By binding to the EGF-A domain of Ldlr, Pcsk9 targets this receptor for lysosomal degradation rather than for recycling to the cell surface.20,21”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [20] Lo Surdo, 2011, Mechanistic implications for LDL receptor degradation from the PCSK9/LDLR structure at neutral pH, EMBO Rep source
- cites [21] Lagace, 2006, Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice, J Clin Invest source
The Figure 2 and Figure 3 passages report PCSK9-mediated LDLR degradation and reduced cell-surface LDLR in hepatocytes. They do not establish that the degradation is lysosomal rather than recycling to the surface; the paper also shows binding to the LDLR extracellular domain, not specifically the EGF-A domain. Page numbers are unavailable in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measured
- Findingown data
Co-administration of exogenous active Pcsk9 (3 ng ml−1) with SRT3025 attenuated the drug-dependent increase in Ldlr protein expression in AML12 hepatocytes.
“Co-administration of Pcsk9 [3 ng ml−1, based upon concentrations measured in the supernatants of untreated AML12 (Figure 4D)] and SRT3025 to AML12 hepatocytes attenuated the drug-dependent increase in Ldlr protein expression (Figure 5A).”
Quote in the paperSubstantial claim- Rests on an assumption: AML12 hepatocytes are a valid model of murine hepatocyte Pcsk9 and Ldlr regulation.
- Findingown data
Incubation of AML12 cells with 10 μM SRT3025 was associated with a time-dependent decrease in Pcsk9 secretion into the supernatant.
“Incubation of AML12 cells with 10 μM SRT3025 was associated with a time-dependent decrease in Pcsk9 secretion into the supernatant (Figure 4D).”
Quote in the paperSubstantial claim- Rests on an assumption: AML12 hepatocytes are a valid model of murine hepatocyte Pcsk9 and Ldlr regulation.
- Findingown data
SRT3025 treatment increased liver expression of Abca1 in Apoe−/− mice.
“Pharmacological Sirt1 activation increased liver expression of Abca1, but did not affect Abcg5, Abcg8, Ldlr, Pcsk9, Pparα, Pparγ, Srebp1, and Srebp2 (Figure 3A).”
Quote in the paperNot a substantial claim - Findingown data
SRT3025 treatment reduced hepatic mRNA expression of Mcp-1 and Il-6 in Apoe−/− mice.
“In addition, we observed reduced plasma levels of Mcp-1 and Il-6 (Figure 1G) and lower hepatic mRNA expression of these cytokines (Figure 3A).”
Quote in the paperNot a substantial claim - Findingown data
SRT3025 treatment increased deacetylation of hepatic p65 and skeletal muscle Foxo1 in Apoe−/− mice.
“Increased deacetylation of known Sirt1 targets upon SRT3025 treatment, hepatic p65 and forkhead transcription factor family O1 (Foxo1) in skeletal muscle (Figure 2B and C) indicate successful Sirt1 activation in vivo.”
Quote in the paperSubstantial claim - Findingown data
SRT3025 treatment reduced plasma Pcsk9 protein levels in Apoe−/− mice compared with placebo-treated controls.
“In agreement with this, we found reduced plasma Pcsk9 protein levels following pharmacological Sirt1 activation in Apoe−/− mice compared with placebo-treated controls (Figure 3C).”
Quote in the paperSubstantial claim - Findingown data
SRT3025 treatment lowered plasma total-, LDL-, and VLDL-cholesterol in Apoe−/− mice compared with placebo.
“Interestingly, plasma levels of total-, LDL- and VLDL-cholesterol were significantly lower after SRT3025 treatment compared with placebo (Figure 1E and F).”
Quote in the paperSubstantial claim - Findingown data
Pcsk9 binding to Ldlr was impaired after 24 h incubation with 10 μM SRT3025 compared with vehicle control in AML12 cells.
“Moreover, co-immunoprecipitation of endogenous Pcsk9 and Ldlr after 24 h incubation with 10 μM SRT3025 revealed that Pcsk9 binding to Ldlr was impaired after SRT3025 treatment compared with vehicle control (Figure 4E).”
Quote in the paperSubstantial claim- Rests on an assumption: AML12 hepatocytes are a valid model of murine hepatocyte Pcsk9 and Ldlr regulation.
- Findingown data
SRT3025 treatment increased labelled LDL uptake in AML12 cells compared with vehicle controls.
“Fluorescence analysis revealed an increase in labelled LDL uptake upon 10 μM SRT3025 treatment compared with vehicle controls (Figure 5B), suggesting a functional relevance of the SRT3025-dependent increase in Ldlr expression.”
Quote in the paperSubstantial claim- Rests on an assumption: AML12 hepatocytes are a valid model of murine hepatocyte Pcsk9 and Ldlr regulation.
- Findingown data
In Ldlr−/− mice, SRT3025 treatment did not affect plasma LDL-cholesterol, HDL-cholesterol, and triglycerides.
“Plasma lipids showed an increase in total and VLDL-cholesterol in SRT3025-treated Ldlr−/− mice compared with placebo-treated controls (Figure 7E and F), whereas plasma LDL-cholesterol, HDL-cholesterol, and triglycerides were unaffected by drug treatment (Figure 7F and Supplementary material online, Figure S2A).”
Quote in the paperSubstantial claim - Findingown data
Genetic overexpression of Sirt1 increased Ldlr protein expression in AML12 cells compared with control transfection.
“Conversely, genetic overexpression of Sirt1 increased Ldlr protein expression in AML12 cells compared with control transfection (Figure 6B).”
Quote in the paperSubstantial claim- Rests on an assumption: AML12 hepatocytes are a valid model of murine hepatocyte Pcsk9 and Ldlr regulation.
- Findingown data
Baseline plasma Pcsk9 levels in Ldlr−/− mice were about 20-fold higher than in Apoe−/− mice.
“Compared with Apoe−/− mice, baseline plasma Pcsk9 levels in Ldlr−/− mice were about 20-fold higher (Figure 7G).”
Quote in the paperNot a substantial claim - Findingown data
SRT3025 treatment reduced plaque size in thoraco-abdominal aortae en face and aortic root cross-sections in Apoe−/− mice compared with placebo-treated controls.
“Histomorphometry of thoraco-abdominal aortae en face and cross-sections of aortic roots revealed a significant reduction in plaque size in SRT3025-treated Apoe−/− mice compared with placebo-treated controls (Figure 1A and B).”
Quote in the paperSubstantial claim - Findingown data
In Ldlr−/− mice, SRT3025 treatment lowered plasma levels of pro-inflammatory cytokines Mcp-1 and Il-6.
“As in Apoe−/− mice, SRT3025 prevented an increase in weight gain and epididymal white adipose tissue without affecting food intake (Supplementary material online, Figure S2B–D), and lowered plasma levels of pro-inflammatory cytokines Mcp-1 and Il-6 (Figure 7G).”
Quote in the paperNot a substantial claim - Findingown data
SRT3025 treatment induced a minimal but significant increase in plasma Pcsk9 levels in Ldlr−/− mice.
“SRT3025 induced a minimal but significant increase in plasma Pcsk9 levels in Ldlr−/− mice (Figure 7G).”
Quote in the paperNot a substantial claim - Findingown data
SRT3025 did not alter mRNA levels of Ldlr and Pcsk9 in AML12 cells.
“As observed in vivo, mRNA levels of Ldlr and Pcsk9 were not altered by SRT3025 (Figure 4C), indicating that post-translational effects cause the changes in protein expression.”
Quote in the paperSubstantial claim- Rests on an assumption: AML12 hepatocytes are a valid model of murine hepatocyte Pcsk9 and Ldlr regulation.
- Findingown data
Pharmacokinetic analysis showed that SRT3025 reached target tissues in Apoe−/− mice.
“Pharmacokinetic analysis of the drug in Apoe−/− mice showed that the drug indeed reached target tissues (Supplementary material online, Table S1).”
Quote in the paperNot a substantial claim - Findingown data
SRT3025 administration increased Ldlr and Pcsk9 protein expression in AML12 hepatocyte lysates in a concentration- and time-dependent manner.
“We observed a concentration- and time-dependent increase in Ldlr and Pcsk9 protein expression upon SRT3025 administration in cell lysates (Figure 4A and B).”
Quote in the paperSubstantial claim- Rests on an assumption: AML12 hepatocytes are a valid model of murine hepatocyte Pcsk9 and Ldlr regulation.
- Findingown data
SRT3025 treatment reduced plasma levels of Mcp-1 and Il-6 in Apoe−/− mice.
“In addition, we observed reduced plasma levels of Mcp-1 and Il-6 (Figure 1G) and lower hepatic mRNA expression of these cytokines (Figure 3A).”
Quote in the paperSubstantial claim - Findingown data
In Ldlr−/− mice, SRT3025 treatment increased plasma total and VLDL-cholesterol compared with placebo-treated controls.
“Plasma lipids showed an increase in total and VLDL-cholesterol in SRT3025-treated Ldlr−/− mice compared with placebo-treated controls (Figure 7E and F), whereas plasma LDL-cholesterol, HDL-cholesterol, and triglycerides were unaffected by drug treatment (Figure 7F and Supplementary material online, Figure S2A).”
Quote in the paperSubstantial claim - Findingown data
SRT3025 treatment did not affect hepatic mRNA expression of Abcg5, Abcg8, Ldlr, Pcsk9, Pparα, Pparγ, Srebp1, and Srebp2 in Apoe−/− mice.
“Pharmacological Sirt1 activation increased liver expression of Abca1, but did not affect Abcg5, Abcg8, Ldlr, Pcsk9, Pparα, Pparγ, Srebp1, and Srebp2 (Figure 3A).”
Quote in the paperSubstantial claim - Findingown data
Sirt1 knockdown in AML12 cells prevented the SRT3025-induced increase in Ldlr expression.
“In contrast to control scramble siRNA-treated cells, cells transfected with Sirt1 siRNA did not show an increase in Ldlr expression upon SRT3025 addition (Figure 6A).”
Quote in the paperSubstantial claim- Rests on an assumption: AML12 hepatocytes are a valid model of murine hepatocyte Pcsk9 and Ldlr regulation.
- Findingown data
In Ldlr−/− mice, SRT3025 treatment did not change the extent of atherosclerosis in thoraco-abdominal aortae en face and aortic root cross-sections compared with placebo.
“Plaque analyses of thoraco-abdominal aortae en face and cross-sections of aortic roots revealed no difference in the extent of atherosclerosis between drug- and placebo-treated mice (Figure 7A and B).”
Quote in the paperSubstantial claim - Findingown data
Co-administration of exogenous active Pcsk9 attenuated the SRT3025-induced increase in LDL uptake in AML12 cells.
“Moreover, co-administration of exogenous active Pcsk9 also attenuated the drug-induced increase in LDL uptake (Figure 5B), consistent with the observed attenuation of Ldlr protein expression (Figure 5A).”
Quote in the paperSubstantial claim- Rests on an assumption: AML12 hepatocytes are a valid model of murine hepatocyte Pcsk9 and Ldlr regulation.
- Interpretationreasoning
The intracellular accumulation of Pcsk9 protein with no change in mRNA suggests a disturbed transport and/or secretion of the protein.
“This intracellular accumulation of Pcsk9 protein with no change in mRNA suggests a disturbed transport and/or secretion of the protein.”
Quote in the paperSubstantial claim - Interpretationown data
The internalization and degradation process of Ldlr is not defective in SRT3025-treated AML12 cells.
“These data indicate that the internalization and degradation process of Ldlr is not defective and that limited extracellular availability of Pcsk9 contributes to the increase in Ldlr protein expression.”
Quote in the paperSubstantial claim- Rests on an assumption: AML12 hepatocytes are a valid model of murine hepatocyte Pcsk9 and Ldlr regulation.
- Interpretationown data
SRT3025 impairs Pcsk9 binding to hepatic Ldlr.
“These data indicate that SRT3025 decreases hepatic Pcsk9 release, impairs Pcsk9 binding to hepatic Ldlr, and thereby prevents hepatic Ldlr degradation.”
Quote in the paperSubstantial claim - Interpretationown data
Reduction in Pcsk9 secretion is a novel effect of Sirt1 activity.
“We identify reduction in Pcsk9 secretion as a novel effect of Sirt1 activity and uncover Ldlr as a prerequisite for Sirt1-mediated atheroprotection in mice.”
Quote in the paperSubstantial claim - Interpretationown data
Not the reduction in inflammation, which still occurs in the absence of Ldlr, but the decrease in plasma LDL-cholesterol accounted for reducing atherosclerosis in Apoe−/− mice treated with SRT3025.
“Therefore, our data suggest that not the reduction in inflammation, which still occurs in the absence of Ldlr, but the decrease in plasma LDL-cholesterol accounted for reducing atherosclerosis in Apoe−/− mice treated with SRT3025.”
Quote in the paperSubstantial claim - Interpretationown data
SRT3025 decreases hepatic Pcsk9 release.
“These data indicate that SRT3025 decreases hepatic Pcsk9 release, impairs Pcsk9 binding to hepatic Ldlr, and thereby prevents hepatic Ldlr degradation.”
Quote in the paperSubstantial claim- Rests on an assumption: Plasma Pcsk9 levels reflect hepatic Pcsk9 secretion in mice.
- Interpretationown data
The atherosclerotic phenotype in SRT3025-treated mice is independent of changes in body weight.
“Moreover, since we observed a reduction in weight gain in both Apoe−/− and Ldlr−/− mice despite unaltered food intake, the atherosclerotic phenotype is also independent of changes in body weight.”
Quote in the paperNot a substantial claim - Interpretationown data
SRT3025 prevents hepatic Ldlr degradation.
“These data indicate that SRT3025 decreases hepatic Pcsk9 release, impairs Pcsk9 binding to hepatic Ldlr, and thereby prevents hepatic Ldlr degradation.”
Quote in the paperSubstantial claim - Interpretationown data
Ldlr is a prerequisite for Sirt1-mediated atheroprotection in mice.
“We identify reduction in Pcsk9 secretion as a novel effect of Sirt1 activity and uncover Ldlr as a prerequisite for Sirt1-mediated atheroprotection in mice.”
Quote in the paperSubstantial claim - Interpretationown data
The SRT3025-associated changes in Ldlr expression are Sirt1-dependent.
“These data indicate that the SRT3025-associated changes in Ldlr expression are Sirt1-dependent.”
Quote in the paperSubstantial claim- Rests on an assumption: AML12 hepatocytes are a valid model of murine hepatocyte Pcsk9 and Ldlr regulation.
- Premisecitation
Genetic overexpression of Sirt1 in Ldlr−/− mice enhanced atherosclerosis.
“Sirt1 has been shown to be atheroprotective in apolipoprotein E-deficient (Apoe−/−) mice2–4 whereas genetic overexpression of Sirt1 in LDL-receptor-deficient (Ldlr−/−) mice enhanced atherosclerosis.5”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [5] Qiang, 2011, Proatherogenic abnormalities of lipid metabolism in SirT1 transgenic mice are mediated through Creb deacetylation, Cell Metab source
Checked before — its earlier verdict is held back until a new check runs.
- Interpretationown data
Limited extracellular availability of Pcsk9 contributes to the increase in Ldlr protein expression in SRT3025-treated AML12 cells.
“These data indicate that the internalization and degradation process of Ldlr is not defective and that limited extracellular availability of Pcsk9 contributes to the increase in Ldlr protein expression.”
Quote in the paperSubstantial claim- Rests on an assumption: AML12 hepatocytes are a valid model of murine hepatocyte Pcsk9 and Ldlr regulation.
- Interpretationown data
Sirt1 is required for SRT3025-induced increase in Ldlr protein expression.
“Thus, Sirt1 is required for SRT3025-induced increase in Ldlr protein expression.”
Quote in the paperSubstantial claim- Rests on an assumption: AML12 hepatocytes are a valid model of murine hepatocyte Pcsk9 and Ldlr regulation.
- Interpretationown data
Increased expression of hepatic Ldlr is essential for the cholesterol-lowering effects of SRT3025.
“Taken together, we demonstrate that the increased expression of hepatic Ldlr is essential for the cholesterol-lowering effects of SRT3025.”
Quote in the paperSubstantial claim
- It may state two separate claims as one. 12
- Probably not a substantial claim. 4
- The quote only partly states this claim. 1
It may state two separate claims as one.
PremisecitationSecreted Pcsk9 targets hepatic Ldlr for lysosomal degradation and prevents recycling of internalized Ldlr to the cell surface.
“Secreted Pcsk9 targets hepatic Ldlr for lysosomal degradation and thus prevents recycling of internalized Ldlr to the cell surface.14”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [14] Zaid, 2008, Proprotein convertase subtilisin/kexin type 9 (PCSK9): hepatocyte-specific low-density lipoprotein receptor degradation and critical role in mouse liver regeneration, Hepatology source
The introductory passage says secreted PCSK9 binds LDLR and favors its targeting to endosomes/lysosomes for degradation; the Results also show that PCSK9 deficiency increases hepatocyte cell-surface LDLR. Our copy does not state that recycling of internalized LDLR is prevented. A title in the References says receptor recycling is decreased, which is narrower than the claim's 'prevents recycling.' (LLM, conf=0.84)
Experimental — accuracy not yet measured
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationClinical studies with another Sirt1 activator have shown a reduction in plasma total cholesterol and LDL-cholesterol.
“In line with our findings, clinical studies with another Sirt1 activator have shown a reduction in plasma total cholesterol and LDL-cholesterol.8,9”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [8] Libri, 2012, A pilot randomized, placebo controlled, double blind phase I trial of the novel SIRT1 activator SRT2104 in elderly volunteers, PLoS One source
- cites [9] Venkatasubramanian, 2013, Cardiovascular effects of a novel SIRT1 activator, SRT2104, in otherwise healthy cigarette smokers, J Am Heart Assoc source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationAntibody-induced inhibition of Pcsk9 binding to Ldlr is currently investigated as a promising therapy to reduce plasma LDL-cholesterol and atherosclerosis in patients.
“Antibody-induced inhibition of Pcsk9 binding to Ldlr is currently investigated as a very promising therapy to reduce plasma LDL-cholesterol and atherosclerosis in patients.24,25”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [24] Chan, 2009, A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates, Proc Natl Acad Sci USA source
The Abstract reports that the antibody blocks PCSK9–LDLR binding and lowers LDL cholesterol in monkeys; the Discussion describes its potential as a treatment for patients. The study did not test the antibody in patients or show that it reduces atherosclerosis, so those parts of the claim go beyond this source. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [25] Ling, 2012, Novel strategies for managing dyslipidemia: treatment beyond statins, Postgrad Med source
It may state two separate claims as one.
Findingown dataDespite no changes in Ldlr and Pcsk9 mRNA expression, both Ldlr and Pcsk9 were markedly increased at the protein level in livers of SRT3025-treated Apoe−/− mice.
“Despite no changes in Ldlr and Pcsk9 mRNA expression, both were markedly increased at the protein level (Figure 3A and B).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataSRT3025 concentration-dependently activated wild-type Sirt1 but failed to activate the activation-resistant Sirt1 mutant E230K in vitro.
“SRT3025 concentration-dependently activated wild-type Sirt1, but failed to activate the activation-resistant Sirt1 mutant E230K in vitro (Figure 2A).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataSRT3025 treatment reduced Cd68-positive macrophages within the plaque and Vcam-1 expression in aortic roots in Apoe−/− mice.
“Moreover, a marked reduction of Cd68-positive macrophages within the plaque and Vcam-1 expression in aortic roots was observed (Figure 1C and D).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataSRT3025 treatment prevented an increase in weight gain and epididymal white adipose tissue without affecting food intake in Apoe−/− mice.
“SRT3025 prevented an increase in weight gain and epididymal white adipose tissue without affecting food intake, thereby mimicking a caloric restriction phenotype (Supplementary material online, Figure S1B–D).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataIn Ldlr−/− mice, SRT3025 treatment prevented an increase in weight gain and epididymal white adipose tissue without affecting food intake.
“As in Apoe−/− mice, SRT3025 prevented an increase in weight gain and epididymal white adipose tissue without affecting food intake (Supplementary material online, Figure S2B–D), and lowered plasma levels of pro-inflammatory cytokines Mcp-1 and Il-6 (Figure 7G).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataSRT3025 treatment did not change plasma triglycerides and HDL-cholesterol in Apoe−/− mice.
“Triglycerides and HDL-cholesterol remained unchanged (Supplementary material online, Figure S1A).”
Quote in the paperNot a substantial claimIt may state two separate claims as one. The quote only partly states this claim.
Findingown dataIn Ldlr−/− mice, SRT3025 treatment decreased expression of Pparα but did not affect Abcg5, Abcg8, Abca1, Pcsk9, Pparγ, Srebp1, Srebp2, Mcp-1 and Il-6.
“Pharmacological Sirt1 activation decreased the expression of Pparα, but did not affect Abcg5, Abcg8, Abca1, Pcsk9, Pparγ, Srebp1, Srebp2, Mcp-1 and Il-6 (Supplementary material online, Figure S2E).”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Findingown dataPlasma protein levels of glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, and alkaline phosphatase were not different between SRT3025- and placebo-treated Apoe−/− mice.
“Plasma protein levels of glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, and alkaline phosphatase were not different between drug- and placebo-treated mice (Supplementary material online, Figure S1E).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataIn Ldlr−/− mice, SRT3025 treatment did not change the number of plaque-resident macrophages (Cd68) and Vcam-1 expression in aortic roots.
“Furthermore, the number of plaque-resident macrophages (Cd68) and Vcam-1 expression in aortic roots did not differ between the groups (Figure 7C and D).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
InterpretationreasoningSRT3025 increases hepatic Ldlr expression and enhances LDL-cholesterol plasma clearance.
“These events result in increased hepatic Ldlr expression and enhanced LDL-cholesterol plasma clearance.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataSirt1 activation increases hepatic Ldlr protein expression through a reduction in Pcsk9-mediated Ldlr degradation leading to decreased plaque formation.
“We demonstrate that Sirt1 activation increases hepatic Ldlr protein expression through a reduction in Pcsk9-mediated Ldlr degradation leading to decreased plaque formation.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataSRT3025 administration to Apoe−/− mice provides atheroprotection and reduces plasma LDL-cholesterol and inflammation.
“These findings indicate that SRT3025 administration to Apoe−/− mice provides atheroprotection and reduces plasma LDL-cholesterol and inflammation.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationTranscription of Ldlr is controlled by Srebp2.
“Transcription of Ldlr is controlled by the sterol-responsive element binding protein 2 (Srebp2),12 while its turnover depends on proprotein convertase subtilisin/kexin type 9 (Pcsk9), a serine protease.13”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [12] Sudhof, 1987, 42 bp element from LDL receptor gene confers end-product repression by sterols when inserted into viral TK promoter, Cell source
The paper relies on this without support.
Plasma Pcsk9 levels reflect hepatic Pcsk9 secretion in mice.
“In agreement with this, we found reduced plasma Pcsk9 protein levels following pharmacological Sirt1 activation in Apoe−/− mice compared with placebo-treated controls (Figure 3C).”
The paper relies on this without support.
AML12 hepatocytes are a valid model of murine hepatocyte Pcsk9 and Ldlr regulation.
“To delineate the mechanisms by which SRT3025 affects Ldlr protein expression, we performed in vitro experiments administering SRT3025 to mouse hepatoma AML12 cells.”
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?
Pharmacological activation of intracellular SIRT1 in cultured hepatocytes enhances hepatic LDLR levels by regulating PCSK9 in a post-translational manner.
“In our previous study,17 we provide evidence that pharmacological activation of intracellular Sirtuin-1 (SIRT1) in cultured hepatocytes enhanced hepatic LDLR levels by regulating PCSK9 in a post-translational manner.17”
From Sirtuin-1 directly binds and deacetylates hepatic PCSK9 thereby promoting the inhibition of LDL receptor degradation (2025) · cites this paper as [17]
Small molecule activators of intracellular SIRT1 reduced total cholesterol and especially plasma LDL-C levels.
“Small molecule activators of intracellular SIRT1 reduced total cholesterol35 and especially plasma LDL-C levels.17”
From Sirtuin-1 directly binds and deacetylates hepatic PCSK9 thereby promoting the inhibition of LDL receptor degradation (2025) · cites this paper as [17]
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.
Discussion says plasma Pcsk9 was unchanged in Ldlr−/− mice
MinorThe discussion includes plasma Pcsk9 among the variables it says were unchanged in Ldlr−/− mice. The results instead report a significant increase in plasma Pcsk9 after SRT3025 treatment.
“None of these variables were changed in Ldlr−/− mice despite a similar decrease in systemic inflammation.”
“SRT3025 induced a minimal but significant increase in plasma Pcsk9 levels in Ldlr−/− mice (Figure 7G).”
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Metadata
- Authors
- Miranda, M. X., van Tits, L. J., Lohmann, C., Arsiwala, T., Winnik, S., Tailleux, A., Stein, S., Gomes, A. P., Suri, V., Ellis, J. L., Lutz, T. A., Hottiger, M. O., Sinclair, D. A., Auwerx, J., Schoonjans, K., Staels, B., Lüscher, T. F., & Matter, C. M.
- Affiliations
- University of Zurich (CH)
- Inserm (FR)
- Harvard University (US)
- École Polytechnique Fédérale de Lausanne (CH)
- Corresponding author
- Matter, Christian M.
- ORCID
- Venue
- European Heart Journal
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-03-06
- Volume
- 36
- Issue
- 1
- Pages
- 51-59
- ISSN
- 0195-668X (ISSN-L)
- 1522-9645
- PMC
- PMC4286317
- OpenAlex
- W2158618709
- Semantic Scholar
- b483cadffc141d6cb4c2d383bbeb4fb0b4321efb
- Cited by
- 153
- References
- 25
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 11 · 2023: 12 · 2022: 14 · 2021: 20 · 2020: 16 · 2019: 7 · 2018: 15 · 2017: 10 · 2016: 10 · 2015: 17 · 2014: 4
- FWCI
- 5.82
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by-nc
- Locations
- European Heart Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
- reroDoc Digital Library (submittedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- National Institute on Aging (R37AG028730)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Keywords
- SIRT1, atherosclerosis, PCSK9, LDL receptor, LDL cholesterol, ApoE-deficient mice, high-cholesterol diet, hepatic lipid metabolism, FOXO1, LDL uptake, atheroprotection
- MeSH terms
- Proprotein Convertase 9, Anilides, Animals, Anticholesteremic Agents, Apolipoproteins E, Arteriosclerosis, Cells, Cultured, Enzyme Inhibitors, Cholesterol, LDL, Male, Mice, Inbred C57BL, Receptors, LDL, RNA, Messenger, Serine Endopeptidases, Thiazoles, Hepatocytes, Proprotein Convertases, Sirtuin 1, In Vitro Techniques
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.
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