Sirtuin-1 directly binds and deacetylates hepatic PCSK9 thereby promoting the inhibition of LDL receptor degradation

Velagapudi, Srividya; Miranda, Melroy X; Adla, Priyanka; Kraler, Simon; Mohammed, Shafeeq A; Baki, Shekhar; Robert, Jerome; Rohrer, Lucia; Lee, Hwan; Jang, Hyun-Duk; Obeid, Slayman; Tailleux, Anne; Staels, Bart; Sepuri, Naresh Babu V; Paneni, Francesco; Gutti, Ravi Kumar; von Eckardstein, Arnold; Kim, Hyo-Soo; Akhmedov, Alexander; Camici, Giovanni G; Lüscher, Thomas F

doi:10.1093/cvr/cvaf087

Cited by 4Sirtuins and Resveratrol in MedicineCholesterol and Lipid MetabolismLipoproteins and Cardiovascular Health

The DOI matches its Crossref record; 43 of the 43 references it cites were found in a registry or an index; 3 of the 39 sources its claims cite were checked for support.

Sirtuin-1 directly binds and deacetylates hepatic PCSK9 thereby promoting the inhibition of LDL receptor degradation

Open access

Velagapudi, Srividya, Miranda, Melroy X, Adla, Priyanka, Kraler, Simon, Mohammed, Shafeeq A, Baki, Shekhar, Robert, Jerome, Rohrer, Lucia, Lee, Hwan, Jang, Hyun-Duk, Obeid, Slayman, Tailleux, Anne, Staels, Bart, Sepuri, Naresh Babu V, Paneni, Francesco, Gutti, Ravi Kumar, von Eckardstein, Arnold, Kim, Hyo-Soo, Akhmedov, Alexander, Camici, Giovanni G, Lüscher, Thomas F·2025·Cardiovascular Research

DOI 10.1093/cvr/cvaf087PMC PMC12352300

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Abstract

Aims: Low-density lipoprotein (LDL)-cholesterol is causally involved in atherosclerotic cardiovascular disease (ASCVD) pathogenesis. Pharmacological activation of the intracellular NAD + -dependent deacetylase Sirtuin-1 (SIRT1) reduces plasma LDL-cholesterol levels by increasing hepatic LDL-receptor (LDLR) expression, which intriguingly associates with atheroprotective effects. Recent studies have identified the presence of SIRT1 in plasma, however, its effects remain elusive. We found that plasma levels of SIRT1 to be decreased in atherosclerotic mice compared with wild-type controls and aimed to investigate the therapeutic potential of systemic SIRT1 restoration on lipid metabolism and plaque burden in atherosclerotic mice and dissect the underlying molecular mechanisms involved. Methods and results: Twelve-week-old apolipoprotein E-deficient (ApoE−/−) mice fed a high-cholesterol diet (1.25% w/w) were randomized to receive recombinant murine SIRT1(rmSIRT1) (n = 6; 0.3 mg/kg BW i.p.) or vehicle (n = 6; PBS) every third day over 4 weeks. Boosting systemic SIRT1 levels increased hepatic LDLR protein expression, reduced plasma LDL-cholesterol levels and decreased plaque progression in ApoE−/− mice. Yet, rmSIRT1 treatment did not change hepatic proprotein convertase subtilisin/kexin type 9 (PCSK9) expression but notably increased its deacetylated levels. Mechanistically, rmSirt1 directly bound to hepatic PCSK9 thereby promoting PCSK9 deacetylation involving 3 sites, namely Lys243, Lys421, and Lys506, as shown by mass spectrometric analyses. In vitro mutagenesis to triple deacetylation mimetic (3KR) reduced SIRT1-induced PCSK9 activity, as evidenced by increased cellular binding and association of 125I-LDL to hepatic LDLR. Finally, plasma levels of SIRT1 and PCSK9 were assessed at baseline in patients with acute coronary syndromes. In these patients, plasma SIRT1 levels correlated inversely with PCSK9 with high SIRT1 levels conferring a reduced risk of major adverse cardiovascular events (MACE). Conclusion: SIRT1 directly binds hepatic PCSK9 and decreases its activity by deacetylation, thereby enhancing LDL-cholesterol clearance by hepatic LDLR upregulation. Boosting circulating SIRT1 exerts atheroprotective effects in mice, with high levels associating with improved prognosis in patients with established ASCVD.

AI snapshot

Written from the paper’s full text.

TL;DR

In ApoE−/− mice on a high-cholesterol diet, recombinant murine SIRT1 restored circulating SIRT1, increased hepatic LDLR, lowered LDL-cholesterol and plaque burden, and directly bound/deacetylated PCSK9 at Lys243, Lys421, and Lys506. In ACS patients, plasma SIRT1 correlated inversely with PCSK9, and the highest SIRT1 tertile was associated with reduced 1-year MACE risk.

Key findings

rmSIRT1 treatment (0.3 mg/kg i.p. every third day for 4 weeks) restored plasma SIRT1 in ApoE−/− mice (17.35 ± 1.731 ng/mL, n = 4, P = 0.002) versus untreated ApoE−/− mice (6.988 ± 0.6512 ng/mL, n = 4), compared with wild-type controls (25.48 ± 2.326 ng/mL, n = 4, P = 0.0003).
rmSIRT1 increased hepatic LDLR protein, reduced total cholesterol, LDL-cholesterol, and VLDL-cholesterol, left HDL-cholesterol unchanged, and reduced aortic plaque size, CD68-positive macrophage accumulation, and pro-atherogenic cytokines; total hepatic/plasma PCSK9 was unchanged, but acetyl-PCSK9 was decreased.
SIRT1 directly bound PCSK9 by SPR with an equilibrium dissociation constant of 35 nM (abstract; Figure 4 reports 34 nM), and mass spectrometry identified four PCSK9 acetylation sites, with rhSIRT1 deacetylating Lys243, Lys421, and Lys506 but not Lys273; the deacetylation mimetic PCSK9-3KR failed to reduce LDLR, whereas acetylation mimetic PCSK9-3KQ mimicked wild-type PCSK9.
In 168 ACS patients, plasma SIRT1 inversely correlated with PCSK9 (R = −0.1753, P = 0.0262; STEMI r = −0.2306, P = 0.0297); 32 MACE occurred over 1 year, and the highest SIRT1 tertile had adjusted HR 0.36 (95% CI 0.15–0.88, P = 0.0242) after sex/age adjustment, with similar multivariable and sensitivity results.

Methods

Male ApoE−/− C57BL/6J mice were fed a 1.25% cholesterol diet for 4 weeks, then randomized at 12 weeks to rmSIRT1 (0.3 mg/kg i.p. every third day) or vehicle for 4 weeks (n = 6 per group); plasma lipids, aortic plaque, liver lipids, and PCSK9 acetylation were assessed.
Huh7 human hepatoma cells were treated with rhSIRT1 (1 μmol/L), rhPCSK9 (2 μg/mL), LDLR siRNA, or PCSK9 WT/3KR/3KQ mutants; assays included 125I-LDL binding/association, immunoprecipitation, deacetylation, SPR binding, and mass spectrometry.
A sub-cohort of 168 ACS patients from the SPUM-ACS study (NCT01000701) had plasma SIRT1 and PCSK9 measured by ELISA; Pearson correlation and Kaplan-Meier/Cox models assessed 1-year MACE.

Limitations

Stated: only male mice were used because sex reportedly had no notable effect on circulating SIRT1, but female atherosclerotic mice remain to be tested; the rmSIRT1 dose was based on in vitro experiments, and future liver-targeted delivery is planned.
Stated: human findings are observational, with limited sample size, no subgroup analyses to avoid model overfit, and possible residual confounding; acetylated/deacetylated PCSK9 ratios could not be measured in human samples because acetyl-lysine PCSK9 peptides were not detected without prior enrichment and plasma volumes were limited.
Evident from the text: mouse experiments used small groups (n = 6 per group, with some ELISA n = 4), and the human SIRT1–MACE association is correlational, so causality is not established.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1093/cvr/cvaf087

Cites

43 of 43 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

3 of 39 cited sources checked · 2 supported · 0 flagged · accuracy not yet measured

Findingown data
SIRT1 directly binds hepatic PCSK9.
“Mechanistically, rmSirt1 directly bound to hepatic PCSK9 thereby promoting PCSK9 deacetylation involving 3 sites, namely Lys243, Lys421, and Lys506, as shown by mass spectrometric analyses.”
- Also stated in: § Conclusion · plain
  “SIRT1 directly binds hepatic PCSK9 and decreases its activity by deacetylation, thereby enhancing LDL-cholesterol clearance by hepatic LDLR upregulation.”
Quote in the paperSubstantial claim
Findingown data
In Huh7 cells, rhSIRT1 treatment does not affect total media PCSK9 levels.
“pre-treatment of Huh7 cells with 1 μmol/L of rhSIRT1 for 2 h did not affect total PCSK9 levels neither in lysed cells nor in the collected cell-culture media (Figure 2D, E)”
Quote in the paperNot a substantial claim
Findingown data
rmSIRT1 treatment diminishes accumulation of CD68 positive cells in aortic roots of ApoE−/− mice.
“and diminished accumulation of CD68 positive cells (Figure 1I).”
Quote in the paperSubstantial claim
Findingown data
Silencing LDLR decreases 125I-LDL cellular binding and association in Huh7 cells.
“silencing LDLR alone decreased 125I-LDL cellular binding and association (Figure 3A and B).”
Quote in the paperSubstantial claim
Findingown data
SIRT1 deacetylates PCSK9 at three sites: Lys243, Lys421, and Lys506.
“Mechanistically, rmSirt1 directly bound to hepatic PCSK9 thereby promoting PCSK9 deacetylation involving 3 sites, namely Lys243, Lys421, and Lys506, as shown by mass spectrometric analyses.”
Quote in the paperSubstantial claim

Findingown data
rmSIRT1 treatment reduces plaque size in thoracic-abdominal aortae and aortic roots of ApoE−/− mice.
“decreased plaque progression in ApoE−/− mice”
- Also stated in: § rmSIRT1 decreases LDL-C, reduces inflammation, and provides athero-protection in ApoE−/− mice · plain
  “en face preparations of the thoracic-abdominal aortae and cross-sections of aortic roots of rmSIRT1-treated ApoE−/− mice showed reduced plaque size (Figures 1F–H)”
Quote in the paperSubstantial claim
Findingown data
High SIRT1 levels are associated with reduced risk of major adverse cardiovascular events (MACE) in patients with acute coronary syndromes.
“In these patients, plasma SIRT1 levels correlated inversely with PCSK9 with high SIRT1 levels conferring a reduced risk of major adverse cardiovascular events (MACE).”
- Also stated in: § Conclusion · plain
  “with high levels associating with improved prognosis in patients with established ASCVD.”
Quote in the paperSubstantial claim
Findingown data
Pre-treatment of Huh7 cells with rhSIRT1 increases specific cellular association of 125I-LDL at 37°C.
“Pre-treatment of Huh7 cells with 1 μmol/L of rhSIRT1 for 2 h increased the specific cellular association of 125I-LDL at 37°C (Figure 3A)”
Quote in the paperSubstantial claim
Findingown data
rmSIRT1 treatment does not change hepatic PCSK9 protein levels in ApoE−/− mice.
“did not change hepatic proprotein convertase subtilisin/kexin type 9 (PCSK9) expression”
- Also stated in: § rmSIRT1 increases hepatic LDLR by deacetylation of PCSK9 in ApoE−/− mice · plain
  “To assess whether rmSIRT1 affects hepatic LDLR expression through PCSK9 protein levels, we assessed hepatic and plasma PCSK9 levels and observed no difference between rmSIRT1− and vehicle-treated mice (Figure 2A and B).”
Quote in the paperSubstantial claim
Findingown data
rmSIRT1 treatment decreases hepatic triglyceride levels in ApoE−/− mice.
“Moreover, the levels of hepatic triglycerides (see Supplementary material online, Figure S4B) and total cholesterol (see Supplementary material online, Figure S4C) were also decreased in the tissue lysates of the mice treated with rmSIRT1.”
Quote in the paperSubstantial claim
Findingown data
rmSIRT1 treatment does not change plasma PCSK9 levels in ApoE−/− mice.
“To assess whether rmSIRT1 affects hepatic LDLR expression through PCSK9 protein levels, we assessed hepatic and plasma PCSK9 levels and observed no difference between rmSIRT1− and vehicle-treated mice (Figure 2A and B).”
Quote in the paperSubstantial claim
Findingown data
rhSIRT1 does not restore cellular binding and association of 125I-LDL inhibited by LDLR suppression in Huh7 cells.
“pre-treatment with 1 μmol/L of rhSIRT1 for 2 h did not restore the cellular binding and association of 125I-LDL, inhibited by the suppression of LDLR (Figure 3A and B).”
Quote in the paperSubstantial claim
Findingown data
Exogenous SIRT1 inhibits PCSK9-mediated LDLR degradation in hepatocytes.
“Exogenous SIRT1 inhibits PCSK9-mediated LDLR degradation in hepatocytes”
Quote in the paperSubstantial claim
Findingown data
Plasma SIRT1 levels correlate inversely with PCSK9 in patients with acute coronary syndromes.
“In these patients, plasma SIRT1 levels correlated inversely with PCSK9 with high SIRT1 levels conferring a reduced risk of major adverse cardiovascular events (MACE).”
Quote in the paperSubstantial claim
Findingown data
rmSIRT1 treatment prevents body weight gain in ApoE−/− mice.
“rmSIRT1 prevented body weight gain (Figure 1B)”
Quote in the paperNot a substantial claim
Findingown data
rmSIRT1 treatment does not change HDL-cholesterol levels in ApoE−/− mice.
“whereas HDL-cholesterol (see Supplementary material online, Figure S3B) levels remained unchanged.”
Quote in the paperNot a substantial claim
Findingown data
rmSIRT1 treatment decreases plasma total cholesterol in ApoE−/− mice.
“treatment of ApoE−/− mice with rmSIRT1 decreased plasma levels of total cholesterol (Figure 1C and D)”
Quote in the paperSubstantial claim
Findingown data
rmSIRT1 treatment decreases lipid deposits in hepatic sections of ApoE−/− mice.
“treatment with rmSIRT1 showed decreased lipid deposits in the hepatic sections compared with the vehicle-treated ApoE−/− mice (see Supplementary material online, Figure S4A).”
Quote in the paperSubstantial claim
Findingown data
rmSIRT1 treatment decreases expression of pro-atherogenic cytokines IL-1β, IL-6, TNF-α and IFN-γ in ApoE−/− mice.
“In line, expression of the pro-atherogenic cytokines IL-1β, IL-6, TNF-α and IFN-γ (see Supplementary material online, Figure S3C), as assessed using cytokine profiler assay and plasma levels of RANTES, a marker for atherogenesis and fibrosis (see Supplementary material online, Figure S3D), were decreased in the plasma of ApoE−/− mice treated with rmSIRT1.”
Quote in the paperSubstantial claim
Findingown data
Treatment with rmSIRT1 restores plasma SIRT1 levels in ApoE−/− mice.
“resulting in restored plasma SIRT1 levels in ApoE−/− mice (17.35 ± 1.731 ng/mL, n = 4, P = 0.002) (Figure 1A).”
Quote in the paperSubstantial claim
Findingown data
rmSIRT1 treatment decreases plasma VLDL-cholesterol in ApoE−/− mice.
“and VLDL-cholesterol (see Supplementary material online, Figure S3A)”
Quote in the paperNot a substantial claim
Findingown data
rmSIRT1 treatment improves glucose tolerance in ApoE−/− mice.
“improved glucose tolerance (see Supplementary material online, Figure S2A and B)”
Quote in the paperNot a substantial claim
Findingown data
In Huh7 cells, rhSIRT1 treatment does not affect total cellular PCSK9 levels.
“pre-treatment of Huh7 cells with 1 μmol/L of rhSIRT1 for 2 h did not affect total PCSK9 levels neither in lysed cells nor in the collected cell-culture media (Figure 2D, E)”
Quote in the paperNot a substantial claim
Findingown data
Plasma SIRT1 levels are decreased in ApoE−/− mice fed a high-cholesterol diet compared with wild-type controls.
“We found that plasma levels of SIRT1 to be decreased in atherosclerotic mice compared with wild-type controls”
- Also stated in: § rmSIRT1 restores reduced plasma levels and decreases body weight in ApoE−/− mice · plain
  “Plasma levels of circulating SIRT1 were decreased in ApoE−/− mice fed a high-cholesterol diet (mean ± SEM; 6.988 ± 0.6512 ng/mL, n = 4) as compared with wild-type controls (25.48 ± 2.326 ng/mL, n = 4, P = 0.0003) (Figure 1A).”
Quote in the paperSubstantial claim
Findingown data
In Huh7 cells, rhSIRT1 treatment reduces acetyl-PCSK9 levels in the media.
“the levels of acetyl-PCSK9 were reduced in the media of rhSIRT1-treated cells compared with the vehicle-treated Huh7 cells (Figure 2F)”
Quote in the paperSubstantial claim
Findingown data
rmSIRT1 treatment decreases plasma LDL-cholesterol in ApoE−/− mice.
“reduced plasma LDL-cholesterol levels”
- Also stated in: § rmSIRT1 decreases LDL-C, reduces inflammation, and provides athero-protection in ApoE−/− mice · plain
  “LDL-cholesterol (Figure 1E)”
Quote in the paperSubstantial claim
Findingown data
rmSIRT1 treatment increases hepatic LDLR protein expression in ApoE−/− mice.
“Boosting systemic SIRT1 levels increased hepatic LDLR protein expression”
- Also stated in: § rmSIRT1 increases hepatic LDLR by deacetylation of PCSK9 in ApoE−/− mice · plain
  “Notably, this was associated with an increased total hepatic LDLR protein expression relative to vehicle-treated controls (Figure 2A).”
Quote in the paperSubstantial claim
Findingown data
rmSIRT1 treatment decreases plasma RANTES levels in ApoE−/− mice.
“In line, expression of the pro-atherogenic cytokines IL-1β, IL-6, TNF-α and IFN-γ (see Supplementary material online, Figure S3C), as assessed using cytokine profiler assay and plasma levels of RANTES, a marker for atherogenesis and fibrosis (see Supplementary material online, Figure S3D), were decreased in the plasma of ApoE−/− mice treated with rmSIRT1.”
Quote in the paperNot a substantial claim
Findingown data
rmSIRT1 treatment improves insulin levels in ApoE−/− mice.
“and insulin levels (see Supplementary material online, Figure S2C) in ApoE−/− mice.”
Quote in the paperNot a substantial claim
Findingown data
rmSIRT1 treatment decreases hepatic total cholesterol levels in ApoE−/− mice.
“Moreover, the levels of hepatic triglycerides (see Supplementary material online, Figure S4B) and total cholesterol (see Supplementary material online, Figure S4C) were also decreased in the tissue lysates of the mice treated with rmSIRT1.”
Quote in the paperSubstantial claim
Findingown data
rmSIRT1 treatment decreases acetyl-PCSK9 levels in plasma of ApoE−/− mice.
“notably increased its deacetylated levels”
- Also stated in: § rmSIRT1 increases hepatic LDLR by deacetylation of PCSK9 in ApoE−/− mice · plain
  “the levels of acetyl-PCSK9 were decreased with rmSIRT1 treatment compared with the vehicle-treated mice (Figure 2C).”
Quote in the paperSubstantial claim
Findingown data
PCSK9 acetylation is modified post-translationally.
“we show for the first time that PCSK9 acetylation is modified post-translationally”
Quote in the paperSubstantial claim
Findingown data
SIRT1-mediated deacetylation sites of PCSK9 are two within the catalytic domain (Lys243, Lys421) and one in the C-terminal domain (Lys506).
“We characterized the SIRT1-mediated deacetylation sites of PCSK9 using mass spectrometry, two within the catalytic domain (Lys243, Lys421) and one in the C-terminal domain (Lys506).”
Quote in the paperSubstantial claim
Findingown data
Deacetylation of rhPCSK9 by pre-incubation with rhSIRT1 in the presence of 5 mM NAD+ reduced the binding of rhPCSK9 to the EGF-A of LDLR.
“deacetylation of rhPCSK9 by pre-incubation with rhSIRT1 in the presence of 5 mM NAD+ reduced the binding of rhPCSK9 to the EGF-A of LDLR”
Quote in the paperSubstantial claim
- The authors state this as an assumption: Substitution of Lys243, Lys421, and Lys506 by glutamine (3KQ) mimics acetylation, and substitution by arginine (3KR) mimics deacetylation.
Findingown data
Kaplan-Meier curves suggested an inverse relationship between SIRT1 plasma levels and event-free survival.
“with Kaplan-Meier curves suggesting an inverse relationship between SIRT1 plasma levels and event-free survival”
Quote in the paperSubstantial claim
Findingown data
The SPR-based assay showed an increase of response units between rhSIRT1 and rhPCSK9 in a dose-dependent manner with an equilibrium dissociation constant of 35 nM.
“The SPR-based assay showed an increase of response units between rhSIRT1 and rhPCSK9 in a dose-dependent manner with an equilibrium dissociation constant of 35 nM”
Quote in the paperSubstantial claim
Findingown data
Transfection of Huh7 cells with acetylation mimetic PCSK9-3KQ decreased the specific cellular binding and association of 125I-LDL.
“transfection of the Huh7 cells with acetylation mimetic PCSK9–3KQ decreased the specific cellular binding and association 125I-LDL”
Quote in the paperSubstantial claim
- The authors state this as an assumption: Substitution of Lys243, Lys421, and Lys506 by glutamine (3KQ) mimics acetylation, and substitution by arginine (3KR) mimics deacetylation.
Findingown data
Transfection with deacetylation mimetic PCSK9-3KR did not affect the specific cellular binding and association of 125I-LDL.
“whereas the transfection with deacetylation mimetic PCSK9–3KR did not affect the specific cellular binding and association 125I-LDL”
Quote in the paperSubstantial claim
- The authors state this as an assumption: Substitution of Lys243, Lys421, and Lys506 by glutamine (3KQ) mimics acetylation, and substitution by arginine (3KR) mimics deacetylation.
Findingown data
In patients presenting with ACS, baseline levels of SIRT1 and PCSK9 are inversely correlated (R = −0.1753, P = 0.0262).
“an inverse correlation between baseline levels of SIRT1 and PCSK9 was observed (R = −0.1753, P = 0.0262)”
Quote in the paperSubstantial claim
Findingown data
Transfection of Huh7 cells with the acetylation mimetic PCSK9-3KQ mimicked the effect of wild-type PCSK9 in reducing LDLR expression in Huh7 cells.
“Transfection of Huh7 cells with the acetylation mimetic PCSK9–3KQ mimicked the effect of wild-type PCSK9 in reducing LDLR expression in Huh7 cells”
Quote in the paperSubstantial claim
- The authors state this as an assumption: Substitution of Lys243, Lys421, and Lys506 by glutamine (3KQ) mimics acetylation, and substitution by arginine (3KR) mimics deacetylation.
Findingown data
High circulating levels of SIRT1 are associated with improved outcomes in patients with established ASCVD.
“Finally, we show that high circulating levels of SIRT1 are associated with improved outcomes in patients with established ASCVD.”
Quote in the paperSubstantial claim
Findingown data
After adjustment for sex and age, patients in the highest SIRT1 tertile had a 64% reduced risk of MACE during 1 year after the index ACS (adjusted HR 0.36, 95% CI 0.15-0.88, P = 0.0242).
“After adjustment for sex and age, patients in the highest SIRT1 tertile had a 64% reduced risk of MACE during 1 year after the index ACS [adjusted HR, 95% confidence interval (CI), 0.36, 0.15–0.88, P = 0.0242]”
Quote in the paperSubstantial claim
Findingown data
Treatment with Brefeldin A and Monensin decreased specific cellular associated 125I-LDL in the presence of rhPCSK9.
“and specific cellular associated 125I-LDL in the presence of rhPCSK9”
Quote in the paperSubstantial claim
Findingown data
Western blotting showed that SIRT1 protein levels were increased.
“Western Blotting showed that SIRT1 protein levels were increased”
Quote in the paperSubstantial claim
Findingown data
Among all patients, 32 MACE occurred during 1 year of follow-up.
“Among all patients, a total of 32 MACE (composite measure of non-fatal myocardial infarction, non-fatal stroke, ischaemia-driven revascularization, in-stent thrombosis, and death from cardiovascular causes) occurred during 1 year of follow-up”
Quote in the paperNot a substantial claim
Findingown data
Similar results were obtained in sensitivity analyses adjusting for sex, age, body mass index and a history of hypertension and/or diabetes (adjusted HR 0.36, 95% CI 0.14-0.90, P = 0.0288).
“Similar results were obtained in sensitivity analyses adjusting for sex, age, body mass index and a history of hypertension and/or diabetes (adjusted HR, 95% CI, 0.36, 0.14–0.90, P = 0.0288).”
Quote in the paperNot a substantial claim
Findingown data
Higher levels of circulating SIRT1 are associated with reduced risk of major adverse cardiovascular events.
“We showed that higher levels of circulating SIRT1 are associated with reduced risk of major adverse cardiovascular events”
Quote in the paperSubstantial claim
Findingown data
Treatment of Huh7 cells with rhPCSK9 reduced cellular binding and association of 125I-LDL in a concentration-dependent manner.
“treatment of Huh7 cells with rhPCSK9 reduced cellular binding and association of 125I-LDL in a concentration-dependent manner”
Quote in the paperSubstantial claim
Findingown data
The deacetylation mimetic PCSK9-3KR failed to reduce LDLR protein expression.
“while the deacetylation mimetic PCSK9–3KR failed to reduce LDLR protein expression”
Quote in the paperSubstantial claim
- The authors state this as an assumption: Substitution of Lys243, Lys421, and Lys506 by glutamine (3KQ) mimics acetylation, and substitution by arginine (3KR) mimics deacetylation.
Findingown data
Huh7 cells pre-treated with rhSIRT1 decreased the expression of acetyl-PCSK9 lysine levels compared with control conditions.
“Huh7 cells pre-treated with rhSIRT1 decreased the expression of acetyl-PCSK9 lysine levels compared with control conditions”
Quote in the paperSubstantial claim
Findingown data
rhSIRT1 is internalised by Huh7 cells.
“The data showed that rhSIRT1 is internalised by the Huh7 cells (see Supplementary material online, Figure S7A).”
Quote in the paperSubstantial claim
Findingown data
Levels of acetyl-PCSK9 were not changed in hepatic tissue lysates.
“the levels of acetyl-PCSK9 were not changed in the hepatic tissue lysates”
Quote in the paperSubstantial claim
Findingown data
Co-incubation of rhPCSK9 (2 μg/mL) with rhSIRT1 (1 μmol/L) in Huh7 cells significantly attenuated LDLR degradation mediated by exogenous PCSK9.
“co-incubation of rhPCSK9 (2 μg/mL) with rhSIRT1 (1 μmol/L) in Huh7 cells significantly attenuated LDLR degradation mediated by exogenous PCSK9”
Quote in the paperSubstantial claim
Findingown data
Similar results were observed in multivariable analyses adjusting for smoking status, estimated glomerular filtration rate and presence of lipid-lowering therapies (adjusted HR 0.26, 95% CI 0.08-0.85, P = 0.0261).
“which was similarly observed in multivariable analyses adjusting for smoking status, estimated glomerular filtration rate and presence of lipid-lowering therapies (adjusted HR, 95% CI, 0.26, 0.08–0.85, P = 0.0261)”
Quote in the paperSubstantial claim
Findingown data
In patients with ACS, SIRT1 expression levels associate with reduced risk of MACE.
“Finally, we show that in patients with ACS, SIRT1 expression levels correlate inversely with PCSK9 and associate with reduced risk of MACE.”
Quote in the paperSubstantial claim
Findingown data
The inverse correlation between SIRT1 and PCSK9 was particularly pronounced in patients with ST-elevation myocardial infarction (r = −0.2306, P = 0.0297).
“which was particularly pronounced in patients with ST-elevation myocardial infarction (r = −0.2306, P = 0.0297)”
Quote in the paperNot a substantial claim
Findingown data
PCSK9 undergoes a post-translational modification by acetylation.
“Here, we report for the first time that PCSK9 undergoes a post-translational modification by acetylation.”
Quote in the paperSubstantial claim
Findingown data
Treatment of Huh7 cells with rhPCSK9 protein for 2 h decreased total LDLR protein expression in a concentration-dependent manner.
“treatment of Huh7 cells with rhPCSK9 protein for 2 h decreased total LDLR protein expression in a concentration-dependent manner”
Quote in the paperSubstantial claim
Findingown data
Mass spectrometry identified 4 acetylation sites on PCSK9: Lys243, Lys273, Lys421 in the catalytic domain and Lys506 in the C-terminal domain.
“we identified 4 acetylation sites, 3 of which in the catalytic domain (Lys243, Lys273, Lys421) and one in the C-terminal domain (Lys506)”
Quote in the paperSubstantial claim
Findingown data
qRT-PCR studies did not show any change in endogenous Sirt1 gene expression.
“qRT-PCR studies did not show any change in the endogenous Sirt1 gene expression”
Quote in the paperSubstantial claim
Findingown data
Co-incubation of rhPCSK9 with rhSIRT1 restored the specific cellular binding of 125I-LDL at 4°C and association of 125I-LDL at 37°C by Huh7 cells.
“co-incubation of rhPCSK9 with rhSIRT1 restored the specific cellular binding of 125I-LDL at 4°C and association of 125I-LDL at 37°C (Figure 3D, 3E) by Huh7 cells”
Quote in the paperSubstantial claim
Interpretationown data
Boosting circulating SIRT1 exerts atheroprotective effects in mice.
“Boosting circulating SIRT1 exerts atheroprotective effects in mice, with high levels associating with improved prognosis in patients with established ASCVD.”
Quote in the paperSubstantial claim
Premisecitation
PCSK9 increases plasma LDL-C levels by directing hepatic LDLR to lysosomes for degradation.
“Proprotein convertase subtilisin/kexin type-9 (PCSK9) increases plasma low-density lipoprotein (LDL) cholesterol (LDL-C) levels by directing hepatic low-density lipoprotein receptor (LDLR) to lysosomes for degradation.1,2”
Quote in the paperSubstantial claim0 of 2 sources checked
- cites [1] 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
- cites [2] Seidah, 2014, PCSK9: a key modulator of cardiovascular health, Circ Res source
Interpretationnone given
High SIRT1 levels associate with improved prognosis in patients with established ASCVD.
“Boosting circulating SIRT1 exerts atheroprotective effects in mice, with high levels associating with improved prognosis in patients with established ASCVD.”
Quote in the paperSubstantial claim
Interpretationown data
SIRT1 increases cellular binding and association of LDL through LDLR in hepatocytes.
“Collectively, these data indicate that SIRT1 increases cellular binding and association of LDL through LDLR in hepatocytes.”
Quote in the paperSubstantial claim
Interpretationown data
SIRT1 may deacetylate PCSK9 in the circulation.
“indicating that SIRT1 may indeed deacetylate PCSK9 in the circulation.”
Quote in the paperSubstantial claim
Premisecitation
PCSK9 modulates plaque formation and thrombosis by enhancing the production of pro-inflammatory cytokines including IL-6, IL-1β, TNF-α and IFN-γ.
“PCSK9 modulates plaque formation and thrombosis by enhancing the production of pro-inflammatory cytokines including IL-6, IL-1β, TNF-α and IFN-γ.38,39”
Quote in the paperSubstantial claim0 of 2 sources checked
- cites [38] Momtazi-Borojeni, 2019, PCSK9 and inflammation: a review of experimental and clinical evidence, Eur Heart J Cardiovasc Pharmacother source
- cites [39] Frostegard, 2022, The role of PCSK9 in inflammation, immunity, and autoimmune diseases, Expert Rev Clin Immunol source
Premisereasoning
Truncated PCSK9 without the C-terminal domain failed to degrade LDLR, indicating that domains in PCSK9 that are not required for binding are essential for PCSK9-mediated degradation of LDLR.
“However, the truncated PCSK9 without the C-terminal domain failed to degrade LDLR, indicating that domains in PCSK9 that are not required for binding are essential for PCSK9-mediated degradation of the LDLR.”
Quote in the paperSubstantial claim
Interpretationown data
Restoration of systemic SIRT1 exerts atheroprotective effects through its interaction with PCSK9.
“Our data suggest that restoration of systemic SIRT1 exerts atheroprotective effects through its interaction with PCSK9.”
Quote in the paperSubstantial claim
Premisecitation
Current monoclonal antibodies that target secreted PCSK9 do not alter levels of atherogenic VLDL-C in plasma.
“The current monoclonal antibodies that target secreted PCSK9 do not alter the levels of atherogenic very low-density lipoprotein cholesterol (VLDL-C) in plasma.36,37”
Quote in the paperSubstantial claim0 of 2 sources checked
- cites [36] Reyes-Soffer, 2017, Effects of PCSK9 inhibition with alirocumab on lipoprotein metabolism in healthy humans, Circulation source
  A check is scheduled.
- cites [37] Watts, 2017, Factorial effects of evolocumab and atorvastatin on lipoprotein metabolism, Circulation source
Study design and conductcitation
Male mice were used in the current study due to the lack of notable effect of sex on the levels of circulating SIRT1.
“Male mice were used in the current study due to the lack of notable effect of sex on the levels of circulating SIRT1.43”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites [43] Opstad, 2022, Changes in circulating sirtuin 1 after bariatric surgery, Nutr Metab Cardiovasc Dis source
Interpretationown data
SIRT1 directly binds to PCSK9.
“Circulating SIRT1 directly binds and deacetylates PCSK9”
Quote in the paperSubstantial claim
Interpretationown data
The phenotypic effects were not due to de novo synthesis.
“indicating these phenotypic effects were not due to the de novo synthesis”
Quote in the paperSubstantial claim
Interpretationown data
PCSK9 acetylation is an essential step to maintain proper PCSK9 function, i.e. directing LDLR towards lysosomal degradation.
“an essential step to maintain proper function i.e. directing LDLR towards lysosomal degradation.”
Quote in the paperNot a substantial claim
Premisecitation
SIRT1 is present in the circulation.
“More recent reports identified SIRT1 in the circulation,18,19”
Quote in the paperSubstantial claim0 of 2 sources checked
- cites [18] Mariani, 2016, Circulating SIRT1 increases after intragastric balloon fat loss in obese patients, Obes Surg source
- cites [19] Mariani, 2018, Inverse association of circulating SIRT1 and adiposity: a study on underweight, normal weight, and obese patients, Front Endocrinol (Lausanne) source
Interpretationown data
SIRT1 deacetylates PCSK9.
“Circulating SIRT1 directly binds and deacetylates PCSK9”
- Also stated in: § Circulating SIRT1 directly binds and deacetylates PCSK9 · plain
  “Incubation of Huh7 cells with rhSIRT1 caused deacetylation of PCSK9 on Lys243, Lys421, and Lys506 but not of Lys273”
Quote in the paperSubstantial claim
Premisecitation
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”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [17] Miranda, 2015, The Sirt1 activator SRT3025 provides atheroprotection in Apoe-/- mice by reducing hepatic Pcsk9 secretion and enhancing Ldlr expression, Eur Heart J source
Interpretationown data
Secretion of cellularly produced SIRT1 is important to inactivate PCSK9 and hence clear circulating LDL-C rather than endogenous SIRT1.
“These data indicate that the secretion of cellularly produced SIRT1 is important to inactivate PCSK9 and hence clear the circulating LDL-C rather than the endogenous SIRT1.”
Quote in the paperSubstantial claim
Interpretationreasoning
SIRT1 is a prognostic marker in patients with ASCVD.
“thus establishing SIRT1 as a prognostic marker in patients with ASCVD.”
Quote in the paperSubstantial claim
Interpretationown data
SIRT1-mediated deacetylation of PCSK9 is essential for its function to direct LDLR to lysosomal degradation.
“confirming that SIRT1-mediated deacetylation of PCSK9 is essential for its function to direct LDLR to lysosomal degradation.”
Quote in the paperSubstantial claim
- The authors state this as an assumption: Substitution of Lys243, Lys421, and Lys506 by glutamine (3KQ) mimics acetylation, and substitution by arginine (3KR) mimics deacetylation.
Interpretationown data
Exogenous rhPCSK9 causes LDLR degradation.
“indicating LDLR degradation by exogenous rhPCSK9”
Quote in the paperSubstantial claim
Interpretationown data
PCSK9 is a direct substrate of SIRT1.
“further confirming that PCSK9 is a direct substrate of SIRT1”
Quote in the paperSubstantial claim

Probably not a substantial claim. 34
It may state two separate claims as one. 30
The quote only partly states this claim. 1

Probably not a substantial claim. The paper’s conclusions may not depend on it.
Premisecitation
Elevated LDL-C levels are linked to an increased risk of ASCVD.
“Elevated LDL-C levels are linked to an increased risk of ASCVD,4,5”
Quote in the paperNot a substantial claim2 of 2 sources checked
- cites [4] Boren, 2020, Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel, Eur Heart J source
- cites [5] Goldstein, 2015, A century of cholesterol and coronaries: from plaques to genes to statins, Cell source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Premisecitation
Aggressive LDL-C lowering reduces coronary plaque burden and reduces the risk of ASCVD-related events.
“aggressive LDL-C lowering reduces coronary plaque burden and reduces the risk of ASCVD-related events.6–8”
Quote in the paperNot a substantial claim1 of 3 sources checked
- cites [6] Raber, 2022, Effect of alirocumab added to high-intensity statin therapy on coronary atherosclerosis in patients with acute myocardial infarction: the PACMAN-AMI randomized clinical trial, JAMA source
- cites [7] Schwartz, 2018, Alirocumab and cardiovascular outcomes after acute coronary syndrome, N Engl J Med source
  The Results (page not provided) report fewer cardiovascular events with alirocumab than with placebo in patients who had a recent acute coronary syndrome. The Methods identify cardiovascular events as the trial’s primary endpoint; the cited paper does not report a reduction in coronary plaque burden, so that part of the claim is unsupported. (LLM, conf=0.89)
  Experimental — accuracy not yet measured
- cites [8] Kraler, 2021, Resilience of the internal mammary artery to atherogenesis: shifting from risk to resistance to address unmet needs, Arterioscler Thromb Vasc Biol source
It may state two separate claims as one.
Findingown data
In vitro mutagenesis to triple deacetylation mimetic (3KR) reduces SIRT1-induced PCSK9 activity, as evidenced by increased cellular binding and association of 125I-LDL to hepatic LDLR.
“In vitro mutagenesis to triple deacetylation mimetic (3KR) reduced SIRT1-induced PCSK9 activity, as evidenced by increased cellular binding and association of 125I-LDL to hepatic LDLR.”
Quote in the paperSubstantial claim
- The authors state this as an assumption: The triple deacetylation mimetic (3KR) mutant mimics deacetylated PCSK9.
It may state two separate claims as one.
Findingown data
Restoration of reduced plasma SIRT1 levels in ApoE−/− atherosclerotic mice decreases plasma LDL-C levels, pro-inflammatory cytokines, and hence plaque burden.
“Indeed, we found that restoration of the reduced plasma SIRT1 levels in ApoE−/− atherosclerotic mice decreases plasma LDL-C levels, pro-inflammatory cytokines, and hence plaque burden.”
Quote in the paperSubstantial claim
It may state two separate claims as one.
Findingown data
Systemic SIRT1 replenishment by recombinant SIRT1 delivery decreases pro-atherosclerotic signatures, leading to diminished plaque burden in ApoE−/− mice.
“Our data suggest that systemic SIRT1 replenishment by recombinant SIRT1 delivery decreases pro-atherosclerotic signatures, leading to diminished plaque burden in ApoE−/− mice.”
Quote in the paperSubstantial claim
It may state two separate claims as one.
Findingown data
Incubation of Huh7 cells with rhSIRT1 caused deacetylation of PCSK9 on Lys243, Lys421, and Lys506 but not of Lys273.
“Incubation of Huh7 cells with rhSIRT1 caused deacetylation of PCSK9 on Lys243, Lys421, and Lys506 but not of Lys273”
Quote in the paperSubstantial claim
It may state two separate claims as one.
Findingown data
Incubation with rhSIRT1 in the presence of inhibitors abolished the effects of rhPCSK9, i.e. rhSIRT1 restored the specific cellular association of 125I-LDL.
“incubation with rhSIRT1 in the presence of inhibitors abolished the effects of rhPCSK9, i.e. rhSIRT1 restored the specific cellular association of 125I-LDL”
Quote in the paperSubstantial claim
The quote only partly states this claim.
Findingown data
Treatment with Brefeldin A and Monensin decreased the presence of SIRT1 in the culture medium as assessed by ELISA.
“We found decreased presence of SIRT1 in the culture medium as assessed by the ELISA”
Quote in the paperSubstantial claim
It may state two separate claims as one.
Findingnone given
Treatment with SIRT1 effectively reduced levels of both atherogenic lipoproteins (LDL-C and VLDL-C) and pro-inflammatory cytokines.
“Indeed, treatment with SIRT1 effectively reduced the levels of both atherogenic lipoproteins (LDL-C and VLDL-C) and pro-inflammatory cytokines, a crucial step in the prevention of ASCVD progression.”
Quote in the paperSubstantial claim
It may state two separate claims as one.
Findingreasoning
Elevated acetyl-PCSK9 in plasma of atherosclerotic mice decreases the clearance of LDL-C as evidenced by enhanced degradation of hepatic LDLR.
“In fact, elevated acetyl-PCSK9 in plasma of atherosclerotic mice decreases the clearance of LDL-C as evidenced by enhanced degradation of hepatic LDLR.”
Quote in the paperSubstantial claim
It may state two separate claims as one.
Findingown data
In the current study, boosting circulating SIRT1 levels achieved a significant reduction in LDL-C levels and also reduced systemic inflammation.
“in our current study we achieved a significant reduction in the LDL-C levels by boosting the circulating SIRT1 levels, additionally we also reduced the systemic inflammation”
Quote in the paperSubstantial claim
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Findingown data
Pulling down of PCSK9 from plasma was required to detect the two PCSK9 isoforms.
“Our pilot study showed that pulling down of PCSK9 from plasma was required to detect the two PCSK9 isoforms”
Quote in the paperNot a substantial claim
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Premisecitation
Targeted PCSK9 inhibition restores hepatic LDLR levels, decreases plasma LDL-C levels and improves cardiovascular outcomes.
“targeted PCSK9 inhibition restores hepatic LDLR levels, decreases plasma LDL-C levels and improves cardiovascular outcomes.7,9–11”
Quote in the paperNot a substantial claim0 of 4 sources checked
- cites [7] Schwartz, 2018, Alirocumab and cardiovascular outcomes after acute coronary syndrome, N Engl J Med source
- cites [9] Burke, 2017, PCSK9: regulation and target for drug development for dyslipidemia, Annu Rev Pharmacol Toxicol source
- cites [10] Sabatine, 2017, Evolocumab and clinical outcomes in patients with cardiovascular disease, N Engl J Med source
- cites [11] Ray, 2020, Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol, N Engl J Med source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Premisecitation
PCSK9 is highly expressed in hepatocytes and is synthesized as a zymogen that undergoes autocatalytic processing in the endoplasmic reticulum.
“PCSK9 is highly expressed in hepatocytes and is synthesized as a zymogen that undergoes autocatalytic processing in the endoplasmic reticulum.12,13”
Quote in the paperNot a substantial claim0 of 2 sources checked
- cites [12] Seidah, 2003, The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation, Proc Natl Acad Sci U S A source
- cites [13] Cunningham, 2007, Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia, Nat Struct Mol Biol source
It may state two separate claims as one.
Interpretationown data
SIRT1 directly binds hepatic PCSK9 and decreases its activity by deacetylation, thereby enhancing LDL-cholesterol clearance by hepatic LDLR upregulation.
“SIRT1 directly binds hepatic PCSK9 and decreases its activity by deacetylation, thereby enhancing LDL-cholesterol clearance by hepatic LDLR upregulation.”
Quote in the paperSubstantial claim
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Premisecitation
PCSK9 undergoes a series of post-translational modifications.
“While PCSK9 is known to undergo a series of post-translational modifications,16”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites [16] Dewpura, 2011, Analyses of PCSK9 post-translational modifications using time-of-flight mass spectrometry, Methods Mol Biol source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Study design and conductreasoning
Given the prospective design of the SPUM-ACS study, plasma volumes are limited, and acetylated/deacetylated ratios could not be assessed in this study.
“given the prospective design of the SPUM-ACS study, plasma volumes are limited, and acetylated/deacetylated ratios could not be assessed in this current study.”
Quote in the paperNot a substantial claim
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone given
Protein identifications were accepted if they achieved an FDR less than 1.0% and contained at least 2 identified peptides.
“Protein identifications were accepted if they achieved an FDR less than 1.0% and contained at least 2 identified peptides.”
Quote in the paperNot a substantial claim
It may state two separate claims as one.
Interpretationown data
Boosting circulating SIRT1 levels is a feasible and effective strategy to increase plasma LDL-C clearance and decrease inflammation during atherosclerosis.
“Here, we unveiled boosting circulating SIRT1 levels as a feasible and effective strategy to increase plasma LDL-C clearance and decrease inflammation during atherosclerosis.”
Quote in the paperSubstantial claim
Probably not a substantial claim. It may be too vague to check against evidence.
Interpretationreasoning
Targeting PCSK9 deacetylation through strategies that increase systemic SIRT1 levels could open therapeutic avenues for the regulation of lipid metabolism and inflammation to eventually reduce the risk of ASCVD progression.
“Targeting PCSK9 deacetylation through strategies that increase systemic SIRT1 levels could open exciting therapeutic avenues for the regulation of lipid metabolism and inflammation to eventually reduce the risk of ASCVD progression.”
Quote in the paperNot a substantial claim
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown data
The SIRT1-MACE association was tested independently from sex, age, body mass index and a history of hypertension and/or diabetes in sensitivity analyses.
“In sensitivity analyses and to avoid model overfit, the SIRT1-MACE association was tested independently from sex, age, body mass index and a history of hypertension and/or diabetes”
Quote in the paperNot a substantial claim
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone given
Peptide identifications were accepted if they achieved an FDR less than 0.1% by the Scaffold Local FDR algorithm.
“Peptide identifications were accepted if they achieved an FDR less than 0.1% by the Scaffold Local FDR algorithm.”
Quote in the paperNot a substantial claim
It may state two separate claims as one.
Interpretationown data
Circulating, rather than intracellular SIRT1 exerts lipid-lowering and atheroprotective effects by acting as a novel binding and deacetylase partner of PCSK9 in the circulation.
“indicating that circulating, rather than intracellular SIRT1 exerts lipid-lowering and atheroprotective effects by acting as a novel binding and deacetylase partner of PCSK9 in the circulation.”
Quote in the paperSubstantial claim
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Premisecitation
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”
Quote in the paperNot a substantial claim0 of 2 sources checked
- cites [35] Feng, 2018, SIRT1 activator E1231 protects from experimental atherosclerosis and lowers plasma cholesterol and triglycerides by enhancing ABCA1 expression, Atherosclerosis source
- cites [17] Miranda, 2015, The Sirt1 activator SRT3025 provides atheroprotection in Apoe-/- mice by reducing hepatic Pcsk9 secretion and enhancing Ldlr expression, Eur Heart J source
Probably not a substantial claim. It may state two separate claims as one.
Premisecitation
Upon intracellular processing, PCSK9 is secreted from hepatocytes where it binds extracellularly to the EGF-A domain of LDLR leading to its lysosomal degradation.
“Upon intracellular processing, PCSK9 is secreted from hepatocytes where it binds extracellularly to the epidermal growth factor-A (EGF-A) domain of LDLR leading to its lysosomal degradation.14,15”
Quote in the paperSubstantial claim0 of 2 sources checked
- cites [14] Seidah, 2017, The proprotein convertases in hypercholesterolemia and cardiovascular diseases: emphasis on proprotein convertase Subtilisin/Kexin 9, Pharmacol Rev source
- cites [15] Kwon, 2008, Molecular basis for LDL receptor recognition by PCSK9, Proc Natl Acad Sci U S A source
It may state two separate claims as one.
Premisecitation
Post-translational modifications on PCSK9 affect its half-life and ability to bind and/or direct LDLR to hepatic lysosomes.
“These post-translational modifications on PCSK9 affect its half-life and ability to bind and/or direct LDLR to hepatic lysosomes;41”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [41] Ben Djoudi Ouadda, 2019, Ser-phosphorylation of PCSK9 (Proprotein Convertase Subtilisin-Kexin 9) by Fam20C (family with sequence similarity 20, member C) kinase enhances its ability to degrade the LDLR (low-density lipoprotein receptor), Arterioscler Thromb Vasc Biol source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductcitation
Means were taken by evaluating at least 4 serial cryosections from each mouse.
“Means were taken by evaluating at least 4 serial cryosections from each mouse.28”
Quote in the paperNot a substantial claim
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Premisecitation
Overexpression of Sirt1 in endothelial cells of ApoE−/− mice fed a high-fat diet promotes endothelium-dependent vasodilation and protects against atherosclerosis by increasing eNOS activity.
“overexpression of Sirt1 in endothelial cells of ApoE−/− mice fed on a high-fat diet promotes endothelium-dependent vasodilation and protects against atherosclerosis by increasing eNOS activity.34”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites [34] Zhang, 2008, Endothelium-specific overexpression of class III deacetylase SIRT1 decreases atherosclerosis in apolipoprotein E-deficient mice, Cardiovasc Res source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone given
Transfection efficiency was confirmed using quantitative RT-PCR and Western blotting.
“transfection efficiency was confirmed using quantitative RT-PCR and Western blotting.”
Quote in the paperNot a substantial claim
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone given
At least three independent experiments in triplicates were performed for each experiment.
“At least three independent experiments in triplicates were performed for each experiment.”
Quote in the paperNot a substantial claim
Probably 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 given
The protocol was approved by the local institutional review board, and all study participants gave written informed consent.
“The protocol was approved by the local institutional review board, all study participants gave written informed consent, and all procedures were in accordance with the Declaration of Helsinki.”
Quote in the paperNot a substantial claim
Probably not a substantial claim.
Study design and conductown data
ApoE−/− mice were randomized to receive rmSIRT1 or vehicle.
“At the age of 12 weeks, the mice were randomized to get injected with either vehicle control (Phosphate buffer saline containing 0.1% BSA) or with recombinant murine Sirtuin-1 protein (rmSIRT1, CSB-MP846058MO, Cusabio Biotech, LubioScience, Switzerland) intraperitoneally every third day for 4-weeks (n = 6 per group).”
Quote in the paperSubstantial claim
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown data
Consistent results across different regression models argue for high external validity.
“While the consistent results across different regression models argue for high externally validity”
Quote in the paperNot a substantial claim
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown data
The ACS patient sub-cohort was randomly selected from the SPUM-ACS study.
“A sub-cohort of 168 patients with ACS were randomly selected from the investigator-driven, multicentre SPUM-ACS study (ClinicalTrials.gov Identifier: NCT01000701), a prospective cohort study involving four PCI-capable university hospitals in Switzerland (see Supplementary material online, Figure S4).”
Quote in the paperNot a substantial claim
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone given
The concentration of recombinant SIRT1 injected in atherosclerotic mice was based on the results of in vitro experiments.
“the concentration of recombinant SIRT1 injected in atherosclerotic mice was based on the results of in vitro experiments.”
Quote in the paperNot a substantial claim
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Premisecitation
Current injectable monoclonal antibody therapies block the interaction between PCSK9 and EGF-A of LDLR on the hepatocyte cell surface and decrease plasma LDL-C levels.
“The current injectable monoclonal antibody therapies block the interaction between PCSK9 and EGF-A of the LDLR on the hepatocyte cell surface, decrease plasma LDL-C levels.42”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites [42] Ray, 2019, Pharmacological lipid-modification therapies for prevention of ischaemic heart disease: current and future options, Lancet source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone given
Although a variety of potential confounders were considered in multivariable-adjusted analyses, many other conditions may influence SIRT1 plasma levels and event-free survival alike.
“although a variety of potential confounders were considered in the multivariable-adjusted analyses, there are many other conditions that may influence SIRT1 plasma levels and event-free survival alike.”
Quote in the paperNot a substantial claim
It may state two separate claims as one.
Interpretationown data
SIRT1 treatment is a feasible and effective strategy to restore hepatic LDLR levels and thus increase LDL-C clearance by acting as a binding and deacetylase partner of PCSK9.
“we unveil SIRT1 treatment as a feasible and effective strategy to restore hepatic LDLR levels and thus increase LDL-C clearance by acting as a binding and consequently deacetylase partner of PCSK9.”
Quote in the paperSubstantial claim
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Premisecitation
PCSK9 consists of a pro-domain, catalytic and C-terminal domains and is secreted as a complex containing the cleaved pro-domain non-covalently bound to the mature form.
“PCSK9 consists of a pro-domain, catalytic and C-terminal domains and is secreted as a complex containing the cleaved pro-domain non-covalently bound to the mature form.15”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites [15] Kwon, 2008, Molecular basis for LDL receptor recognition by PCSK9, Proc Natl Acad Sci U S A source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Premisecitation
Intracellular activation of SIRT1 protects against atherosclerosis.
“Mounting evidence has demonstrated that intracellular activation of SIRT1 protects against atherosclerosis.30–33”
Quote in the paperNot a substantial claim0 of 4 sources checked
- cites [30] Stein, 2011, Protective roles of SIRT1 in atherosclerosis, Cell Cycle source
- cites [31] Stein, 2010, SIRT1 decreases Lox-1-mediated foam cell formation in atherogenesis, Eur Heart J source
- cites [32] Winnik, 2012, SIRT1—an anti-inflammatory pathway at the crossroads between metabolic disease and atherosclerosis, Curr Vasc Pharmacol source
- cites [33] Winnik, 2015, Protective effects of sirtuins in cardiovascular diseases: from bench to bedside, Eur Heart J source
It may state two separate claims as one.
Interpretationown data
SIRT1 directly binds to PCSK9 and decreases its activity by deacetylation modification.
“Mechanistically, we showed for the first time that SIRT1 directly binds to PCSK9 and decreases its activity by deacetylation modification.”
Quote in the paperSubstantial claim
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown data
The acetylation/deacetylation ratio of PCSK9 in human samples was not provided because acetylated lysine PCSK9 peptides could not be detected in test cohorts without prior enrichment for acetylated lysines.
“the acetylation/deacetylation ratio of PCSK9 in human samples was not provided as we could not detect acetylated lysine PCSK9 peptides in test cohorts without any prior enrichment for acetylated lysines.”
Quote in the paperNot a substantial claim
Probably not a substantial claim. It may be too vague to check against evidence.
Interpretationown data
Boosting systemic SIRT1 levels may be beneficial in regulating lipid metabolism and inflammation during ASCVD progression.
“Boosting systemic SIRT1 levels may be beneficial in regulating lipid metabolism and inflammation during ASCVD progression.”
Quote in the paperNot a substantial claim
It may state two separate claims as one.
Interpretationown data
SIRT1 decreases the functional activity of PCSK9 and hence prevents hepatic LDLR degradation.
“indicating that SIRT1 decreases the functional activity of PCSK9 and hence prevents hepatic LDLR degradation.”
Quote in the paperSubstantial claim
It may state two separate claims as one.
Interpretationown data
SIRT1-induced direct deacetylation reduces the activity of PCSK9 thereby allowing recycling of hepatic LDLR.
“These findings suggest that SIRT1-induced direct deacetylation reduces the activity of PCSK9 thereby allowing recycling of hepatic LDLR.”
Quote in the paperSubstantial claim
- The authors state this as an assumption: Substitution of Lys243, Lys421, and Lys506 by glutamine (3KQ) mimics acetylation, and substitution by arginine (3KR) mimics deacetylation.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Premisecitation
PCSK9 binds through the catalytic domain to the EGF-A of LDLR on the cell surface in hepatocytes.
“PCSK9 binds through the catalytic domain to the epidermal growth factor-like repeat (EGF-A) of LDLR on the cell surface in hepatocytes.14,15”
Quote in the paperNot a substantial claim0 of 2 sources checked
- cites [14] Seidah, 2017, The proprotein convertases in hypercholesterolemia and cardiovascular diseases: emphasis on proprotein convertase Subtilisin/Kexin 9, Pharmacol Rev source
- cites [15] Kwon, 2008, Molecular basis for LDL receptor recognition by PCSK9, Proc Natl Acad Sci U S A source
It may state two separate claims as one.
Interpretationown data
SIRT1 acts as a novel binding partner of hepatic PCSK9 that inactivates protein function by deacetylation, thereby enhancing LDL-C clearance by upregulating hepatic LDLR expression.
“we provide translational evidence that SIRT1 acts as a novel binding partner of hepatic PCSK9 that inactivates protein function by deacetylation, thereby enhancing LDL-C clearance by upregulating hepatic LDLR expression.”
Quote in the paperSubstantial claim
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Premisecitation
During secretion from hepatocytes, PCSK9 undergoes several post-translational modifications including N-glycosylation, Tyr-sulfation, and phosphorylation.
“During its secretion from hepatocytes, PCSK9 undergoes several post-translational modifications including N-glycosylation, Tyr-sulfation, and phosphorylation.16,41”
Quote in the paperNot a substantial claim0 of 2 sources checked
- cites [16] Dewpura, 2011, Analyses of PCSK9 post-translational modifications using time-of-flight mass spectrometry, Methods Mol Biol source
- cites [41] Ben Djoudi Ouadda, 2019, Ser-phosphorylation of PCSK9 (Proprotein Convertase Subtilisin-Kexin 9) by Fam20C (family with sequence similarity 20, member C) kinase enhances its ability to degrade the LDLR (low-density lipoprotein receptor), Arterioscler Thromb Vasc Biol source
It may state two separate claims as one.
Interpretationreasoning
Deacetylation of PCSK9 by circulating SIRT1 reduces its ability to degrade LDLR and hence aids in efficient clearance of LDL-C from plasma.
“On the other hand, deacetylation of PCSK9 by circulating SIRT1 reduces its ability to degrade LDLR and hence aids in efficient clearance of LDL-C from plasma.”
Quote in the paperSubstantial claim
Probably 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 given
All animal experiments and care procedures were approved by local veterinary authorities and carried out in accordance with institutional guidelines.
“All experiments and animal care procedures were approved by the local veterinary authorities and carried out in accordance with our institutional guidelines (ZH293/14).”
Quote in the paperNot a substantial claim
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductreasoning
Owing to limited sample size and to avoid model overfit, subgroup analyses could not be performed as part of this translational study.
“owing to the limited sample size and to avoid model overfit, subgroup analyses could not be performed as part of this translational study.”
Quote in the paperNot a substantial claim
Probably not a substantial claim.
Premisecitation
Truncated PCSK9 containing only the pro-domain and catalytic domain could still bind to LDLR.
“Previous studies have shown that truncated PCSK9 containing only the pro-domain and catalytic domain could still bind to LDLR.”
Quote in the paperSubstantial claim
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Premisecitation
SIRT1 was measured in the circulation, but its function remains largely unknown.
“Recently, SIRT1 was measured in the circulation19; however, its function remains largely unknown.”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites [19] Mariani, 2018, Inverse association of circulating SIRT1 and adiposity: a study on underweight, normal weight, and obese patients, Front Endocrinol (Lausanne) source

53 of 53

The authors state this as an assumption.
rmSIRT1 is a mimetic for circulating SIRT1 protein.
“rmSIRT1, used as mimetic for circulating SIRT1 protein”
The authors state this as an assumption.
For the clinical data, normality was assumed.
“As regards the clinical data, we assumed normality and Pearson correlation coefficients between PCSK9 and SIRT1 plasma levels were calculated, and a linear regression line was fitted.”
The authors state this as an assumption.
The triple deacetylation mimetic (3KR) mutant mimics deacetylated PCSK9.
“In vitro mutagenesis to triple deacetylation mimetic (3KR) reduced SIRT1-induced PCSK9 activity, as evidenced by increased cellular binding and association of 125I-LDL to hepatic LDLR.”
The paper relies on this without support.
ApoE−/− mice fed a high-cholesterol diet are a valid model of human atherosclerosis/ASCVD.
“Twelve-week-old apolipoprotein E-deficient (ApoE−/−) mice fed a high-cholesterol diet (1.25% w/w) were randomized to receive recombinant murine SIRT1(rmSIRT1) (n = 6; 0.3 mg/kg BW i.p.) or vehicle (n = 6; PBS) every third day over 4 weeks.”
The paper relies on this without support.
The SPUM-ACS sub-cohort of 168 patients with ACS is representative of ACS patients.
“A sub-cohort of 168 patients with ACS were randomly selected from the investigator-driven, multicentre SPUM-ACS study (ClinicalTrials.gov Identifier: NCT01000701), a prospective cohort study involving four PCI-capable university hospitals in Switzerland (see Supplementary material online, Figure S4).”
The paper relies on this without support.
The acetyl-lysine antibody specifically detects acetylated PCSK9 in the ELISA.
“the detection antibody was replaced with acetyl-lysine antibody (9441, CST) for acetyl-PCSK9.”
The authors state this as an assumption.
Substitution of Lys243, Lys421, and Lys506 by glutamine (3KQ) mimics acetylation, and substitution by arginine (3KR) mimics deacetylation.
“Substitution of Lys243, Lys421, and Lys506 by glutamine (K243Q/K421Q/K506Q) in PCSK9–3KQ and arginine (K243R/K421R/K506R) in PCSK9–3KR mimic acetylation and deacetylation, respectively.”
The paper relies on this without support.
The acetylation sites and regulation of PCSK9 observed in cell and mouse models apply to human PCSK9.
“the acetylation/deacetylation ratio of PCSK9 in human samples was not provided as we could not detect acetylated lysine PCSK9 peptides in test cohorts without any prior enrichment for acetylated lysines.”

8 of 8

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

Figure 1A sample sizes conflict
Minor
The Results report n = 4 for each of the three groups whose plasma SIRT1 levels are compared, but the Figure 1A caption reports n = 6 for each group.
SPR dissociation constant differs between Results and caption
Minor
The Results give the Figure 4B equilibrium dissociation constant as 35 nM, while its caption gives 34 nM.
Figure 3A is cited for association but labelled as binding
Minor
The Results cite Figure 3A for cellular association, whereas the figure caption assigns binding to panel A and association to panel B.
Event-free survival relationship has the opposite direction
Minor
An inverse relationship with event-free survival implies worse outcomes at higher SIRT1 levels, contradicting the reported reduced MACE risk in the highest SIRT1 tertile.

4 of 4

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The Role of Sirtuins in Improving Cardiovascular Function and the Prevention of Aging
Duran, R., Parikh, M. A., Raizada, A., Frishman, W. H., & Peterson, S. J. (2025) · Cardiology in Review · doi:10.1097/crd.0000000000001140 · Cited by 2
PCSK9 reloaded: sirtuin-1 as a post-translational checkpoint for LDL-C control
Pirillo, A., & Catapano, A. L. (2025) · Cardiovascular Research · doi:10.1093/cvr/cvaf126
Biomaterials Promote the Regression of Atherosclerotic Plaque by Regulating Cell Behavior
Wang, C., Sun, C., Wu, X., Ding, Z., Liu, K., & Cao, J. (2026) · International Journal of Nanomedicine · doi:10.2147/ijn.s574592
Sirtuins in cardiovascular health
Islam, A., Badruddeen, B., Khan, M. I., Akhtar, J., & Ahmad, A. R. (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-45380-9.00016-x

Sirtuin-1 directly binds and deacetylates hepatic PCSK9 to inhibit low-density lipoprotein receptor degradation
Velagapudi, S., Miranda, M. X., Mohammed, S. A., Kraler, S. C., Robert, J., Rohrer, L., Lee, H., Jang, H. D., Camici, G. G., von Eckardstein, A., et al. (2023) · European Heart Journal · doi:10.1093/eurheartj/ehad655.3285 · Cited by 4
Self-citation
SIRT1 activator SRT3025 provides atheroprotection in ApoE⁻/⁻ mice by increasing hepatic LDL receptor
Miranda, M. X. (2015) · Zurich Open Repository and Archive (University of Zurich) · doi:10.5167/uzh-164462
Self-citation
The novel sirt1 activator srt3025 provides atheroprotection through increased hepatic low-density lipoprotein receptor expression
Miranda, M. X., Lohmann, C., van Tits, L. J., Stein, S., Tailleux, A., Schoonjans, K., Staels, B., Suri, V., Lüscher, T. F., & Matter, C. M. (2013) · European Heart Journal · doi:10.1093/eurheartj/eht308.p2378
Self-citation
SIRT1 activator E1231 protects from experimental atherosclerosis and lowers plasma cholesterol and triglycerides by enhancing ABCA1 expression
Feng, T., Liu, P., Wang, X., Luo, J., Zuo, X., Jiang, X., Liu, C., Li, Y., Li, N., Chen, M., et al. (2018) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2018.04.039 · Cited by 35
PCSK9 inhibition fails to alter hepatic LDLR, circulating cholesterol, and atherosclerosis in the absence of ApoE
Ason, B. L., van der Hoorn, J. W. A., Chan, J. C. Y., Lee, E. W., Pieterman, E. J., Nguyen, K., Di, M., Shetterly, S., Tang, J. T., Yeh, W., et al. (2014) · Journal of Lipid Research · doi:10.1194/jlr.m053207 · Cited by 83

Authors: Velagapudi, S., Miranda, M. X., Adla, P., Kraler, S., Mohammed, S. A., Baki, S., Robert, J., Rohrer, L., Lee, H., Jang, H.-D., Obeid, S., Tailleux, A., Staels, B., Sepuri, N. B. V., Paneni, F., Gutti, R. K., von Eckardstein, A., Kim, H.-S., Akhmedov, A., Camici, G. G., & Lüscher, T. F.
Affiliations: University of Zurich (CH)
University of Hyderabad (IN)
Institute of Clinical Chemistry, University Hospital Zürich , Zürich ,
University Hospital Zurich (CH)
Seoul National University Hospital (KR)
Biomedical Research Institute, Seoul National University Hospital , Seoul ,
Inserm (FR)
King's College London (GB)
Corresponding author: Lüscher, Thomas F
ORCID: Velagapudi, Srividya
Kraler, Simon
Mohammed, Shafeeq A
Rohrer, Lucia
Lee, Hwan
Jang, Hyun-Duk
Obeid, Slayman
Tailleux, Anne
Staels, Bart
Sepuri, Naresh Babu V
Paneni, Francesco
Gutti, Ravi Kumar
von Eckardstein, Arnold
Kim, Hyo-Soo
Akhmedov, Alexander
Camici, Giovanni G
Lüscher, Thomas F
Venue: Cardiovascular Research
Publisher: Oxford University Press (OUP)
Published: 2025-07-14
Volume: 121
Issue: 9
Pages: 1373-1384
ISSN: 0008-6363 (ISSN-L)
1755-3245
DOI: 10.1093/cvr/cvaf087
PMC: PMC12352300
OpenAlex: W4412380612
Cited by: 4
References: 43
Citations by year: 2026: 2 · 2025: 2
FWCI: 2.22
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (am)
Locations: Cardiovascular Research (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by)
Zurich Open Repository and Archive (University of Zurich)
Funders: Swiss National Research Foundation (G.G.C. Nr. 310030_166576, F.P. Nr. 310030_197557)
Swiss Heart Foundation
Theodor Ida Herzog-Egli Foundation
Lindenhofstiftung
Forschungskredit Postdoc grant (S.V. Nr. K-40111-01-01)
Holcim Stiftung grant
Foundation for Cardiovascular Research
National Research Foundation of Korea
Government of Korea (H-D.J. Nr. NRF-2021R1A2C2094323)
Topics: Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
Keywords: SIRT1, PCSK9, protein deacetylation, LDL receptor, LDL cholesterol, atherosclerosis, hepatic lipid metabolism, atherosclerotic plaque, ApoE-deficient mice, acute coronary syndrome, major adverse cardiovascular events, NAD+-dependent deacetylase, LDLR degradation
MeSH terms: Proprotein Convertase 9, Mice, Knockout, ApoE, Acetylation, Animals, Aortic Diseases, Disease Models, Animal, Humans, Cholesterol, LDL, Liver, Male, Mice, Inbred C57BL, Protein Binding, Receptors, LDL, Signal Transduction, Atherosclerosis, Sirtuin 1, Hep G2 Cells, Plaque, Atherosclerotic, Proteolysis

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Sirtuin-1 directly binds and deacetylates hepatic PCSK9 thereby promoting the inhibition of LDL receptor degradation

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