HAL Id: hal-01830973
https://hal.archives-ouvertes.fr/hal-01830973
Submitted on 13 Jul 2018
HAL is a multi-disciplinary open access
archive for the deposit and dissemination of
sci-entific research documents, whether they are
pub-lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.
L’archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d’enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.
Letter From Le May and Cariou Regarding Article,
”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”
Cédric Le May, Bertrand Cariou
To cite this version:
Cédric Le May, Bertrand Cariou. Letter From Le May and Cariou Regarding Article,
”Propro-tein Convertase Subtilisin Kexin Type 9 Promotes Intestinal Overproduction of Triglyceride-Rich
Apolipoprotein B Lipoproteins Through Both LowDensity Lipoprotein ReceptorDependent and
-Independent Mechanisms”. Circulation, 2015, Equipe 5, 131 (18), pp.e427–e427.
�10.1161/CIRCULA-TIONAHA.114.011697�. �hal-01830973�
e427
Correspondence
To the Editor:
We read with interest the article by Rashid and colleagues1 in
Circulation in which they studied the physiological role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in intestinal triglyceride-rich lipoprotein production. In that article, Rashid et al stated that few investigators have characterized the functional importance of PCSK9 in the small intestine and its regulatory role on triglyceride-rich lipo-protein metabolism.1 However, they omitted 2 seminal articles that
previously addressed the question.
We demonstrated and published in 2009 in Arteriosclerosis,
Thrombosis, and Vascular Biology that PCSK9-deficient mice dis-play reduced postprandial hypertriglyceridemia after an olive oil gavage.2 Using the lymph duct cannulation method, we also showed
that PCSK9-deficient mice have reduced intestinal apolipoprotein B production compared with wild-type mice.2 Finally, we confirmed
this relationship between intestinal PCSK9 and apolipoprotein B secretion in vitro in differentiated human Caco-2 cells by showing that adenoviral PCSK9 overexpression or silencing of PCSK9 with targeted SiRNA led to a significant increase or reduction of apolipo-protein B secretion, respectively.2
In 2013, Levy and collaborators3 further confirmed the role of
PCSK9 in lipid metabolism in Caco-2 cells. In their study, they revealed a role for PCSK9 in cholesterol absorption.3 Most important, they
dem-onstrated for the first time that the addition of exogenous PCSK9 in the cultured media of Caco-2 cells significantly alters intestinal apo-lipoprotein B secretion.3 They were also the first to demonstrate that
PCSK9 could affect NPC1L1 expression,3 as reported by Rashid et al.
A second concern is the mode of administration and the dose of exogenous PCSK9 used in the study by Rashid et al. It is unclear in the article whether exogenous PCSK9 was added at the apical or basolateral side of Caco-2 cells, and it must be precised. Levy et al3
have shown that PCSK9 could be secreted at the basolateral side of Caco-2 cells. In contrast, the presence or secretion of PCSK9 at the luminal side of enterocytes is not yet demonstrated. Second, although the authors stated that they added a physiological dose of PCSK9 on Caco-2 cells, plasma circulating PCSK9 mean concentration val-ues were estimated to range from 80 to 4000 ng/mL, depending on the population screened and the type of anti-PCSK9 used in ELISA assays.4 This suggests that the dose chosen is at least 2- to 3-fold
higher than the highest physiological human PCSK9 concentration. In comparison, Levy’s group3 used 4 times less exogenous PCSK9 in
similar experimental conditions.
Disclosures
This work was supported by a grant from Leducq Foundation.
Cedric Le May, PhD INSERM UMR1087-CNRS UMR6291 l’Institut du Thorax Nantes, France Bertrand Cariou, MD, PhD INSERM UMR1087-CNRS UMR6291 l’Institut du Thorax Nantes, France Université de Nantes Faculté de Médecine Institut du Thorax Nantes, France Department of Endocrinology University Hospital of Nantes Nantes, France
References
1. Rashid S, Tavori H, Brown PE, Linton MF, He J, Giunzioni I, Fazio S. Proprotein convertase subtilisin kexin type 9 promotes intesti-nal overproduction of triglyceride-rich apolipoprotein B lipoproteins through both low-density lipoprotein receptor-dependent and -inde-pendent mechanisms. Circulation. 2014;130:431–441. doi: 10.1161/ CIRCULATIONAHA.113.006720.
2. Le May C, Kourimate S, Langhi C, Chétiveaux M, Jarry A, Comera C, Collet X, Kuipers F, Krempf M, Cariou B, Costet P. Proprotein conver-tase subtilisin kexin type 9 null mice are protected from postprandial triglyceridemia. Arterioscler Thromb Vasc Biol. 2009;29:684–690. doi: 10.1161/ATVBAHA.108.181586.
3. Levy E, Ben Djoudi Ouadda A, Spahis S, Sane AT, Garofalo C, Grenier É, Emonnot L, Yara S, Couture P, Beaulieu JF, Ménard D, Seidah NG, Elchebly M. PCSK9 plays a significant role in cholesterol homeosta-sis and lipid transport in intestinal epithelial cells. Atherosclerohomeosta-sis. 2013;227:297–306. doi: 10.1016/j.atherosclerosis.2013.01.023. 4. Cariou B, Le May C, Costet P. Clinical aspects of PCSK9. Atherosclerosis.
2011;216:258–265. doi: 10.1016/j.atherosclerosis.2011.04.018.
(Circulation. 2015;131:e427. DOI: 10.1161/CIRCULATIONAHA.114.011697.)
© 2015 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.114.011697
Letter From Le May and Cariou Regarding
Article, “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”
by guest on July 13, 2018
http://circ.ahajournals.org/
Cedric Le May and Bertrand Cariou
Independent Mechanisms''
−
Dependent and
−
Lipoproteins Through Both Low-Density Lipoprotein Receptor
Kexin Type 9 Promotes Intestinal Overproduction of Triglyceride-Rich Apolipoprotein B
Letter From Le May and Cariou Regarding Article, ''Proprotein Convertase Subtilisin
Print ISSN: 0009-7322. Online ISSN: 1524-4539
Copyright © 2015 American Heart Association, Inc. All rights reserved.
is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Circulation
doi: 10.1161/CIRCULATIONAHA.114.011697
2015;131:e427
Circulation.
http://circ.ahajournals.org/content/131/18/e427
World Wide Web at:
The online version of this article, along with updated information and services, is located on the
http://circ.ahajournals.org//subscriptions/
is online at:
Circulation
Information about subscribing to
Subscriptions:
http://www.lww.com/reprints
Information about reprints can be found online at:
Reprints:
document.
Permissions and Rights Question and Answer
this process is available in the
click Request Permissions in the middle column of the Web page under Services. Further information about
Office. Once the online version of the published article for which permission is being requested is located,
can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial
Circulation
in
Requests for permissions to reproduce figures, tables, or portions of articles originally published
Permissions:
by guest on July 13, 2018
http://circ.ahajournals.org/
