The main goal of our laboratory is to understand the pathophysiological pathways leading to obesity, atherosclerosis, and cardiovascular disease. We recently identified new genes and proteins that may play a major role in the regulation of adipose tissue and lipid metabolism. Our projects aim to characterize the molecular mechanisms through which these genes and proteins regulate the clearance of lipids and cholesterol bound to low-density lipoproteins, or “bad cholesterol,” and how to use this knowledge to make atherosclerosis regress. For these studies, we use cultured cell lines and transgenic mouse models, and we collaborate with clinical research experts to improve patients care. Our experimental approaches involve the use of many advanced techniques in the area of molecular cloning (e.g., CRISPR-Cas9, adeno-associated virus with tissue-specific tropism), cellular biology (e.g., cell fractionation, confocal microscopy of living cells, electron microscopy) and biochemistry (e.g., analysis of protein-protein interactions, mass spectrometry).
Dr. Gaétan Mayer, PhD, Director
gaetan.mayer@icm-mhi.org
Dr. Annie Demers, Research assistant
annie.demers@icm-mhi.org
Dr. Steve Poirier, Fellowship student
steve.poirier@icm-mhi.org
Mrs. Samaneh Samami, Ph.D. student
samaneh.samami@gmail.com
Dr. Emilienne Ngo Sock, Fellowship student
etsock@yahoo.fr
Mrs Nourhen Mnasri, Ph.D student
mnasri_nourhen@yahoo.fr
Mr Hocine Ait Hamouda, Master student
hocine.ait.hamouda@icm-mhi.org
PCSK9 (proprotein convertase subtilisin/kexin type 9) is the ninth member of proprotein convertases, a family of serine proteases recognized to modulate the activity of hundreds of substrates in the secretory pathway. PCSK9 is a major regulator of low-density lipoproteins (LDL) carrying ~70 % of blood cholesterol (also termed "bad cholesterol") and is of paramount importance for vascular health. PCSK9 binds the LDL receptor on the surface of hepatocytes and induces its degradation in lysosomes preventing internalization of LDL particles and increasing circulating LDL levels, a major risk factor for atherosclerosis. Specific hhuman PCSK9 mutations can protect the carrier against coronary heart disease, while other mutations can cause premature atherosclerosis and heart attack at a very young age. This makes PCSK9 a very attractive target for the development of pharmacological inhibitors aiming to reduce coronary heart disease. Our recent data demonstrate that PCSK9 is able to accelerate the degradation of other important receptors involved in triglyceride metabolism and that its function can be regulated by specific endogenous liver proteins. It is thus important to know more about the mechanism by which PCSK9 increases or decreases blood cholesterol and triglycerides. Our laboratory is interested in elucidating the mechanism of PCSK9 to find better ways to counter its harmful activity by developing new and potent PCSK9 inhibitors. The results of our research projects have a high potential for clinical applications.
Poirier S, Mamarbachi M, Chen WT, Lee AS, Mayer G. (2015) GRP94 regulates circulating cholesterol levels through blockade of PCSK9-induced LDLR degradation. Cell Rep. 2015 Dec; 13:2064–2071.
Demers A, Samami S, Lauzier B, Des Rosiers C, Ngo Sock ET, Ong H, Mayer G. (2015) PCSK9 induces CD36 degradation and impacts long-chain fatty acid uptake and triglyceride metabolism in adipocytes and in mouse liver. Arterioscler Thromb Vasc Biol. 35:2517-2525.
Canuel M, Butkinaree C, Essalmani R, Poirier S, Benjannet S, Asselin MC, Marcinkiewicz J, Chamberland A, Guillemot J, Mayer G, Sisodia S, Jacob Y, Prat A, Seidah NG. (2015) Amyloid precursor-like protein 2 and sortilin do not regulate the PCSK9-mediated low density lipoprotein receptor degradation but interact with each other. J Biol Chem, 290 :18609-18620.
Poirier S, Samami S, Mamarbachi M, Demers A, Chang TY, Vance DE, Hatch GM and Mayer G. (2014) The epigenetic drug 5-azacytidine interferes with cholesterol and lipid metabolism. J Biol Chem. 289:18736-18751. JBC July 4th cover.
Leblond F, Poirier S, Yu C, Duquette N, Mayer G, Thorin E (2014) The anti-hypercholesterolemic effect of low p53 expression protects vascular endothelial function in mice. PLoS ONE. 9: e92394. doi:10.1371/journal.pone.0092394.
Poirier S, Mayer G (2013) The biology of PCSK9 from endoplasmic reticulum to lysosomes: new and emerging pharmacological checkpoints to control LDL-cholesterol. Drug Design, Development and Therapy. 7:1135-1148.
Seidah NG, Poirier S, Denis M, Parker R, Miao B, Mapelli C, Prat A, Wassef H, Davignon J, Hajjar KA, Mayer G (2012) Annexin A2 is a natural extrahepatic inhibitor of the PCSK9-induced LDL receptor degradation. PLoS ONE 7: e41865. doi:10.1371/journal.pone.0041865.
Poirier S*, Mayer G*, Murphy SR, Garver WS, Chang TY, Schu P, Seidah NG (2013) The cytosolic adaptor AP-1A is essential for the trafficking and function of NPC1. Traffic. 14: 458–469. *Co-first authors.
Benjannet S, Luna Saavedra YG, Hamelin J, Asselin MC, Essalmani R, Pasquato A, Lemaire P, Duke G, Miao B, Duclos F, Parker R, Mayer G, Seidah NG. (2010) Effects of the prosegment and PH on the activity of PCSK9: evidence for additional processing events. J Biol Chem. 284:28856-28864.
Mayer G, Poirier S, Seidah NG (2008) Annexin A2 is a C-terminal PCSK9 binding protein that regulates endogenous LDL receptor levels. J Biol Chem. 283:31791-31801
Labonté P, Begley S, Guévin C, Asselin MC, Nassoury N, Mayer G, Prat A, Seidah NG (2009) PCSK9 impedes HCV infection in vitro and modulates liver CD81 expression. Hepatology. 50:17-24. (Cover illustration of the journal).
- Subventions de fonctionnement
- IRSC
- Heart and Stroke Foundation
- Fondation canadienne pour l'innovation (FCI)
- Fonds de recherche Québec- Santé (FRQS)
- Chercheur boursier FRQS Junior 1
- Prix Nouveau Chercheur Jonathan-Ballon, Heart and Stroke Foundation of Canada-Quebec (2011)
- Postdoctoral fellow award, Cardiovascular diseases. CLC/Pfizer. 2008
- Doctoral thesis, Dean's Honor list, Pathology and Cell Biology. Faculté de Médecine, Université de Montréal. 2005
- Academic Gold Medal, Outstanding scholastic achievements. Governor General of Canada. 2000
Membres de l'équipe
Dr. Gaétan Mayer, PhD, Director
gaetan.mayer@icm-mhi.org
Dr. Annie Demers, Research assistant
annie.demers@icm-mhi.org
Dr. Steve Poirier, Fellowship student
steve.poirier@icm-mhi.org
Mrs. Samaneh Samami, Ph.D. student
samaneh.samami@gmail.com
Dr. Emilienne Ngo Sock, Fellowship student
etsock@yahoo.fr
Mrs Nourhen Mnasri, Ph.D student
mnasri_nourhen@yahoo.fr
Mr Hocine Ait Hamouda, Master student
hocine.ait.hamouda@icm-mhi.org
Research projects
PCSK9 (proprotein convertase subtilisin/kexin type 9) is the ninth member of proprotein convertases, a family of serine proteases recognized to modulate the activity of hundreds of substrates in the secretory pathway. PCSK9 is a major regulator of low-density lipoproteins (LDL) carrying ~70 % of blood cholesterol (also termed "bad cholesterol") and is of paramount importance for vascular health. PCSK9 binds the LDL receptor on the surface of hepatocytes and induces its degradation in lysosomes preventing internalization of LDL particles and increasing circulating LDL levels, a major risk factor for atherosclerosis. Specific hhuman PCSK9 mutations can protect the carrier against coronary heart disease, while other mutations can cause premature atherosclerosis and heart attack at a very young age. This makes PCSK9 a very attractive target for the development of pharmacological inhibitors aiming to reduce coronary heart disease. Our recent data demonstrate that PCSK9 is able to accelerate the degradation of other important receptors involved in triglyceride metabolism and that its function can be regulated by specific endogenous liver proteins. It is thus important to know more about the mechanism by which PCSK9 increases or decreases blood cholesterol and triglycerides. Our laboratory is interested in elucidating the mechanism of PCSK9 to find better ways to counter its harmful activity by developing new and potent PCSK9 inhibitors. The results of our research projects have a high potential for clinical applications.
Publications
Poirier S, Mamarbachi M, Chen WT, Lee AS, Mayer G. (2015) GRP94 regulates circulating cholesterol levels through blockade of PCSK9-induced LDLR degradation. Cell Rep. 2015 Dec; 13:2064–2071.
Demers A, Samami S, Lauzier B, Des Rosiers C, Ngo Sock ET, Ong H, Mayer G. (2015) PCSK9 induces CD36 degradation and impacts long-chain fatty acid uptake and triglyceride metabolism in adipocytes and in mouse liver. Arterioscler Thromb Vasc Biol. 35:2517-2525.
Canuel M, Butkinaree C, Essalmani R, Poirier S, Benjannet S, Asselin MC, Marcinkiewicz J, Chamberland A, Guillemot J, Mayer G, Sisodia S, Jacob Y, Prat A, Seidah NG. (2015) Amyloid precursor-like protein 2 and sortilin do not regulate the PCSK9-mediated low density lipoprotein receptor degradation but interact with each other. J Biol Chem, 290 :18609-18620.
Poirier S, Samami S, Mamarbachi M, Demers A, Chang TY, Vance DE, Hatch GM and Mayer G. (2014) The epigenetic drug 5-azacytidine interferes with cholesterol and lipid metabolism. J Biol Chem. 289:18736-18751. JBC July 4th cover.
Leblond F, Poirier S, Yu C, Duquette N, Mayer G, Thorin E (2014) The anti-hypercholesterolemic effect of low p53 expression protects vascular endothelial function in mice. PLoS ONE. 9: e92394. doi:10.1371/journal.pone.0092394.
Poirier S, Mayer G (2013) The biology of PCSK9 from endoplasmic reticulum to lysosomes: new and emerging pharmacological checkpoints to control LDL-cholesterol. Drug Design, Development and Therapy. 7:1135-1148.
Seidah NG, Poirier S, Denis M, Parker R, Miao B, Mapelli C, Prat A, Wassef H, Davignon J, Hajjar KA, Mayer G (2012) Annexin A2 is a natural extrahepatic inhibitor of the PCSK9-induced LDL receptor degradation. PLoS ONE 7: e41865. doi:10.1371/journal.pone.0041865.
Poirier S*, Mayer G*, Murphy SR, Garver WS, Chang TY, Schu P, Seidah NG (2013) The cytosolic adaptor AP-1A is essential for the trafficking and function of NPC1. Traffic. 14: 458–469. *Co-first authors.
Benjannet S, Luna Saavedra YG, Hamelin J, Asselin MC, Essalmani R, Pasquato A, Lemaire P, Duke G, Miao B, Duclos F, Parker R, Mayer G, Seidah NG. (2010) Effects of the prosegment and PH on the activity of PCSK9: evidence for additional processing events. J Biol Chem. 284:28856-28864.
Mayer G, Poirier S, Seidah NG (2008) Annexin A2 is a C-terminal PCSK9 binding protein that regulates endogenous LDL receptor levels. J Biol Chem. 283:31791-31801
Labonté P, Begley S, Guévin C, Asselin MC, Nassoury N, Mayer G, Prat A, Seidah NG (2009) PCSK9 impedes HCV infection in vitro and modulates liver CD81 expression. Hepatology. 50:17-24. (Cover illustration of the journal).
Awards and distinctions
- Subventions de fonctionnement
- IRSC
- Heart and Stroke Foundation
- Fondation canadienne pour l'innovation (FCI)
- Fonds de recherche Québec- Santé (FRQS)
- Chercheur boursier FRQS Junior 1
- Prix Nouveau Chercheur Jonathan-Ballon, Heart and Stroke Foundation of Canada-Quebec (2011)
- Postdoctoral fellow award, Cardiovascular diseases. CLC/Pfizer. 2008
- Doctoral thesis, Dean's Honor list, Pathology and Cell Biology. Faculté de Médecine, Université de Montréal. 2005
- Academic Gold Medal, Outstanding scholastic achievements. Governor General of Canada. 2000