Evidence map›Paper›PMID 25070550›Full record

ArticleCirculation2014

Proprotein convertase subtilisin kexin type 9 promotes intestinal overproduction of triglyceride-rich apolipoprotein B lipoproteins through both low-density lipoprotein receptor-dependent and -independent mechanisms.

Shirya Rashid, Hagai Tavori, Patrick E Brown, MacRae F Linton, Jane He, Ilaria Giunzioni, Sergio Fazio

Erratum issuedOpen access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Circulation, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 61 papers.

0numbers the graph read from it
0cells of the map it votes in
61citing papers in PubMed
19.4field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

61 citing papers in PubMed, 135 citations in OpenAlex.

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  6. CRISPR-Cas9 Targeting PCSK9: A Promising Therapeutic Approach for Atherosclerosis.Journal of cardiovascular translational research · 2025
    Review
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  20. PCSK9 Biology and Its Role in Atherothrombosis.International journal of molecular sciences · 2021
    Review

1 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

7 authors at 1 institution in 2 countries.

Shirya RashidFrom the Department of Pharmacology, Dalhousie University, Halifax, NS, and Saint John, NB, Canada (S.R.); Department of Medicine, Section of Cardiovascular Disease Prevention, Vanderbilt University, Nashville, TN (H.T., M.F.L., J.H., I.G., S.F.); Oregon Health and Science University, Portland (H.T., I.G.); and Department of Biostatistics, Faculty of Medicine, University of Toronto and Cancer Care Ontario, Toronto, ON, Canada (P.E.B.). shirya.rashid@Dal.ca.
Hagai TavoriFrom the Department of Pharmacology, Dalhousie University, Halifax, NS, and Saint John, NB, Canada (S.R.); Department of Medicine, Section of Cardiovascular Disease Prevention, Vanderbilt University, Nashville, TN (H.T., M.F.L., J.H., I.G., S.F.); Oregon Health and Science University, Portland (H.T., I.G.); and Department of Biostatistics, Faculty of Medicine, University of Toronto and Cancer Care Ontario, Toronto, ON, Canada (P.E.B.).
Patrick E BrownFrom the Department of Pharmacology, Dalhousie University, Halifax, NS, and Saint John, NB, Canada (S.R.); Department of Medicine, Section of Cardiovascular Disease Prevention, Vanderbilt University, Nashville, TN (H.T., M.F.L., J.H., I.G., S.F.); Oregon Health and Science University, Portland (H.T., I.G.); and Department of Biostatistics, Faculty of Medicine, University of Toronto and Cancer Care Ontario, Toronto, ON, Canada (P.E.B.).
MacRae F LintonFrom the Department of Pharmacology, Dalhousie University, Halifax, NS, and Saint John, NB, Canada (S.R.); Department of Medicine, Section of Cardiovascular Disease Prevention, Vanderbilt University, Nashville, TN (H.T., M.F.L., J.H., I.G., S.F.); Oregon Health and Science University, Portland (H.T., I.G.); and Department of Biostatistics, Faculty of Medicine, University of Toronto and Cancer Care Ontario, Toronto, ON, Canada (P.E.B.).
Jane HeFrom the Department of Pharmacology, Dalhousie University, Halifax, NS, and Saint John, NB, Canada (S.R.); Department of Medicine, Section of Cardiovascular Disease Prevention, Vanderbilt University, Nashville, TN (H.T., M.F.L., J.H., I.G., S.F.); Oregon Health and Science University, Portland (H.T., I.G.); and Department of Biostatistics, Faculty of Medicine, University of Toronto and Cancer Care Ontario, Toronto, ON, Canada (P.E.B.).
Ilaria GiunzioniFrom the Department of Pharmacology, Dalhousie University, Halifax, NS, and Saint John, NB, Canada (S.R.); Department of Medicine, Section of Cardiovascular Disease Prevention, Vanderbilt University, Nashville, TN (H.T., M.F.L., J.H., I.G., S.F.); Oregon Health and Science University, Portland (H.T., I.G.); and Department of Biostatistics, Faculty of Medicine, University of Toronto and Cancer Care Ontario, Toronto, ON, Canada (P.E.B.).
Sergio FazioFrom the Department of Pharmacology, Dalhousie University, Halifax, NS, and Saint John, NB, Canada (S.R.); Department of Medicine, Section of Cardiovascular Disease Prevention, Vanderbilt University, Nashville, TN (H.T., M.F.L., J.H., I.G., S.F.); Oregon Health and Science University, Portland (H.T., I.G.); and Department of Biostatistics, Faculty of Medicine, University of Toronto and Cancer Care Ontario, Toronto, ON, Canada (P.E.B.).
Dalhousie University · CA

Funding

PCSK9, Lipoprotein receptors, and AtherosclerosisR01HL106845 · NHLBI · VANDERBILT UNIVERSITY · PI FAZIO, SERGIO · 2011 to 2014
$2.0M
NHLBI NIH HHS R01 HL106845NHLBI NIH HHS R01-HL106845
6 · The paper itself

Abstract

backgroundProprotein convertase subtilisin kexin type 9 (PCSK9) promotes the degradation of the low-density lipoprotein (LDL) receptor (LDLR), and its deficiency in humans results in low plasma LDL cholesterol and protection against coronary heart disease. Recent evidence indicates that PCSK9 also modulates the metabolism of triglyceride-rich apolipoprotein B (apoB) lipoproteins, another important coronary heart disease risk factor. Here, we studied the effects of physiological levels of PCSK9 on intestinal triglyceride-rich apoB lipoprotein production and elucidated for the first time the cellular and molecular mechanisms involved. METHODS AND

resultsTreatment of human enterocytes (CaCo-2 cells) with recombinant human PCSK9 (10 μg/mL for 24 hours) increased cellular and secreted apoB48 and apoB100 by 40% to 55% each (P<0.01 versus untreated cells), whereas short-term deletion of PCSK9 expression reversed this effect. PCSK9 stimulation of apoB was due to a 1.5-fold increase in apoB mRNA (P<0.01) and to enhanced apoB protein stability through both LDLR-dependent and LDLR-independent mechanisms. PCSK9 decreased LDLR protein (P<0.01) and increased cellular apoB stability via activation of microsomal triglyceride transfer protein. PCSK9 also increased levels of the lipid-generating enzymes FAS, SCD, and DGAT2 (P<0.05). In mice, human PCSK9 at physiological levels increased intestinal microsomal triglyceride transfer protein levels and activity regardless of LDLR expression.

conclusionsPCSK9 markedly increases intestinal triglyceride-rich apoB production through mechanisms mediated in part by transcriptional effects on apoB, microsomal triglyceride transfer protein, and lipogenic genes and in part by posttranscriptional effects on the LDLR and microsomal triglyceride transfer protein. These findings indicate that targeted PCSK9-based therapies may also be effective in the management of postprandial hypertriglyceridemia.

Indexed as

AnimalsApolipoproteins BCaco-2 CellsCell SurvivalEnterocytesHumansHypertriglyceridemiaIntestinal MucosaIntestinesMice, Inbred C57BLMice, KnockoutProprotein Convertase 9Proprotein ConvertasesReceptors, LDLRNA, Small InterferingSerine EndopeptidasesApolipoproteins BPCSK9 protein, humanPcsk9 protein, mouseProprotein Convertase 9Proprotein ConvertasesReceptors, LDLRNA, Small InterferingSerine EndopeptidasesTriglyceridesapolipoproteinslipidsmolecular biologypathophysiologyreceptors, lipoproteinrisk factors

Identifiers

PMID25070550
PMCPMC4115295
OpenAlexW2066450795

What OpenQuestion holds

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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.