Dr. Michel Chretien

Michel Chrétien, FRS, MD, OC, OQ, OLH

mchretien@ohri.ca



(Français)

Emeritus Scientist, Chronic Disease Program, Ottawa Hospital Research Institute
Professor, Division of Endocrinology & Metabolism. The Ottawa Hospital
Professor, Ottawa Institute of System Biology & Department of Biochemistry, Microbiology and
Immunology, University of Ottawa Faculty of Medicine
Professeur émérite de recherche, Institut de recherches cliniques de Montréal (IRCM)

Honorary Degrees

1980 D.Sc. (Honoris Causa), Université de Liège, Belgique
1992 D.Sc. (Honoris Causa), Université René Descartes, Paris
1996 D.Sc. (Honoris Causa), Université Laurentienne, Sudbury, Ontario
1999 D.Sc. (Honoris Causa), University of Guelph, Ontario
2000 D.Sc. (Honoris Causa), Memorial University, Newfoundland and Labrador

Executive Positions held

1984-1994 Scientific Director and CEO, IRCM
1998-2001 Scientific Director and CEO, Loeb Research Institute (LRI), Ottawa, Ontario

Major Awards/Affiliations

Fellow of the Royal Society (London) (FRS)
Officier de l’Ordre du Canada (OC) et de l’Ordre National du Québec (OQ)
Officier de la Légion d’Honneur de la République Française.

Research Interests

Functional Endoproteolysis & Proprotein Convertases in:

  • Cholesterol metabolism (SKI-1/S1P & PCSK9),
  • Glucose homeostasis, diabetes, obesity (PC1/3, PC2, & PCSK9),
  • Atherosclerosis, cancer, Alzheimer’s disease, & viral infections (furin, PACE4, PC5, & PC7,
  • Fertility (PC4).

Research Accomplishments

In 1967, after I had elucidated the sequence of b and g-lipotropic hormone (b/g-LPH), I proposed the Prohormone Theory, which stipulated that peptide hormones are derived from specific internal cleavages of larger and inactive precursor polypeptides [1]. In subsequent years, this theory extended to neuropeptides, growth factors, receptors, transcription factors and viral proteins. In 1976, I discovered human ß-endorphin, confirming that ß-LPH was its precursor [2]. I also characterized its processing from a larger precursor to multiple bioactive peptides known as proopiomelanocortin (POMC) [3,4] . POMC is now considered the prototypical proprotein in the ever-expanding field of functional endoproteolysis. In 1982, I discovered 7B2 [5], a resident protein of neuroendocrine secretory granules, now known to regulate proteolytic activation of prohormones and proneuropeptides. In 1990, my close collaboration with Drs. Nabil G. Seidah, Majambu Mbikay, and other IRCM colleagues led to the discovery of Proprotein Convertases 1 and 2 (PC1 & PC2) [6] . This was followed by the identification of 5 others of this 9-member family of endoproteinases. PCs, also known as Proprotein Convertases, Subtilisin/Kexin-type (PCSKs) are produced as proenzymes; they self-activate by autocatalytic removal of an N-terminal propeptide. Seven of them cleave their substrates after paired basic residues, as I noted at the sequencing of b-LPH in 1967 [7]. In 1997, Dr. Mbikay in my team produced the PC4KO mouse, the first mouse model of PC genetic deficiency, establishing the crucial role of PC4 in mammalian fertility [8]. In 2003, PCSK9 was discovered [9] and, as a clinical scientist, this seminal observation was professionally very rewarding because of its immediate clinical implications. PCSK9 is an enzyme turned escort protein. It binds the low-density lipoprotein receptor (LDLR) and drives it to destruction, thus reducing LDLR-mediated hepatic clearance of plasma LDL, and increasing its circulating level. PCSK9 is a confirmed target in the treatment of hypercholesterolemia and associated cardiovascular diseases. With Dr. Teik-Chye Ooi, we have studied the correlations of plasma PCSK9 levels with different hormonal status in humans. With Dr. Janice Mayne, we showed that phosphorylation modulates the anti-LDLR activity of PCSK9 [10] . In 2011, I discovered in my own cohort of patients a unique French Canadian mutation that strongly protects against hypercholesterolemia [11] . This dominant negative Q152H variant prevents zymogen auto-cleavage, causing its ER retention. This PCSK9 processing step constitutes a most suitable target for a small-molecule drugs against hypocholesterolemia. Thinking outside the box, Dr. Mbikay has spearheaded two provocative hypotheses stipulating that PCSK9 and its variants may influence resistance to infectious diseases [12] and susceptibility to diabetes [13] . Preliminary experimental and epidemiological evidence support a diabetoprotective role of PCSK9 [13] . Our contributions to the field of functional endoproteolysis in health and disease are described in my recently published short autobiography [7] (Figure. 1).

Ongoing Research Projects

a) PC1/3 and PC2 in body mass and glucose homeostasis. Using mouse models, Dr. Mbikay has shown that PC1/3 deficiency causes obesity and diabetes [14], whereas PC2 deficiency has the opposite effect [15]. We have initiated human studies aimed at examining the possible association of single-nucleotide polymorphisms (SNPs) in PCSK1 and PCSK2 genes with obesity in different populations [16].

b) Search of anti-PCSK9 phytochemicals. PCSK9 is a proven target for a new generation of anti-cholesterol drugs. The study of spontaneous human mutation has provided insights into ways of targeting this protein for inhibition. The Q152H mutation not only prevents PCSK9 maturation and secretion, but, in the heterozygous state, diminishes the secretion of the normal form of the protein, compounding its hypocholesterolemic effect [11] . Small molecules that could replicate these effects could become potent anti-cholesterol drugs. With Dr. Mbikay, we have initiated a program aimed at identifying phytochemicals that could down-regulate one step or another in PCSK9 expression, secretion and function.

c) Protective role of PCSK9 in metabolic syndrome. Metabolic profiling of a female carrier of the potent Q152H mutation suggests that congenital loss of PCSK9 may predispose to prediabetes and adipocyte dysfunction, consistent with observations made in mice by Dr. Mbikay [13] . We will extend this observation  to a larger cohort in collaboration with Dr. May Faraj and her colleagues at the IRCM. We will also investigate the molecular mechanisms of this new PCSK9 function using cell and mouse experimental models.

Collaborations
a) Ethnic PCSK9 phenotypic SNPs. Through national and international collaborations, we are enlarging our search for PCSK9 phenotypic SNPs in Native Canadians, Africans, French, and Chinese populations.

b) PCSK9 and cerebral malaria: To follow-up on Dr. Mbikay’s theory that nonsense PCSK9 mutations protect against lethal infectious diseases, we have initiated a collaboration with Central African scientists to explore a possible association between the African C679X mutation and resistance to cerebral malaria.

c) PCSK9 interactome. With Drs. Janice Mayne and Daniel Figeys at the Ottawa Institute of System Biology, we are now we are conducting unbiased searches for PCSK9 molecular partners using ultra-sensitive proteomics techniques [17] .

Selected Publications


[1] Chrétien M, Li CH. (1967b) Isolation, purification, and characterization of gamma-lipotropic hormone from sheep pituitary glands, Can J Biochem 45: 1163-1174.
[2] Chrétien M, Benjannet S, Dragon N, Seidah NG, Lis M. (1976) Isolation of peptides with opiate activity from sheep and human pituitaries: relationship to beta-lipotropin, Biochem Biophys Res Commun 72: 472-478.
[3] Crine P, Benjannet S, Seidah NG, Lis M, Chrétien M. (1977) In vitro biosynthesis of beta-endorphin, gamma-lipoprotein, and beta-lipotropin by the pars intermedia of beef pituitary glands, Proc Natl Acad Sci U S A 74: 4276-4280.
[4] Chrétien M, Benjannet S, Gossard F, Gianoulakis C, Crine P, Lis M, Seidah NG. (1979) From beta-lipotropin to beta-endorphin and 'pro-opio-melanocortin', Can J Biochem 57: 1111-1121.
[5] Hsi KL, Seidah NG, De Serres G, Chrétien M. (1982) Isolation and NH2-terminal sequence of a novel porcine anterior pituitary polypeptide. Homology to proinsulin, secretin and Rous sarcoma virus transforming protein TVFV60, FEBS Lett 147: 261-266.
[6] Seidah NG, Gaspar L, Mion P, Marcinkiewicz M, Mbikay M, Chrétien M. (1990) cDNA sequence of two distinct pituitary proteins homologous to Kex2 and furin gene products: tissue-specific mRNAs encoding candidates for pro-hormone processing proteinases, DNA Cell Biol 9: 415-424.
[7] Chrétien M. (2012) My road to Damascus: how I converted to the prohormone theory and the proprotein convertases, Biochem Cell Biol 90: 750-768. (An autobiography)
[8] Mbikay M, Tadros H, Ishida N, Lerner CP, De Lamirande E, Chen A, El-Alfy M, Clermont Y, Seidah NG, Chrétien M, Gagnon C, Simpson EM. (1997) Impaired fertility in mice deficient for the testicular germ-cell protease PC4, Proc Natl Acad Sci U S A 94: 6842-6846.
[9] Seidah NG, Benjannet S, Wickham L, Marcinkiewicz J, Jasmin SB, Stifani S, Basak A, Prat A, Chrétien M. (2003) The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): Liver regeneration and neuronal differentiation, Proc Natl Acad Sci U S A 100: 928-933.
[10] Dewpura T, Raymond A, Hamelin J, Seidah NG, Mbikay M, Chrétien M, Mayne J. (2008) PCSK9 is phosphorylated by a Golgi casein kinase-like kinase ex vivo and circulates as a phosphoprotein in humans, Febs J 275: 3480-3493.
[11] Mayne J, Dewpura T, Raymond A, Bernier L, Cousins M, Ooi TC, Davignon J, Seidah NG, Mbikay M, Chrétien M. (2011) Novel loss-of-function PCSK9 variant is associated with low plasma LDL cholesterol in a French-Canadian family and with impaired processing and secretion in cell culture, Clin Chem 57: 1415-1423.
[12] Mbikay M, Mayne J, Seidah NG, Chrétien M. (2007) Of PCSK9, cholesterol homeostasis and parasitic infections: possible survival benefits of loss-of-function PCSK9 genetic polymorphisms, Med Hypotheses 69: 1010-1017.
[13] Mbikay M, Sirois F, Mayne J, Wang GS, Chen A, Dewpura T, Prat A, Seidah NG, Chrétien M, Scott FW. (2010) PCSK9-deficient mice exhibit impaired glucose tolerance and pancreatic islet abnormalities, FEBS Lett 584: 701-706.
[14] Mbikay M, Croissandeau G, Sirois F, Anini Y, Mayne J, Seidah NG, Chrétien M. (2007) A targeted deletion/insertion in the mouse Pcsk1 locus is associated with homozygous embryo preimplantation lethality, mutant allele preferential transmission and heterozygous female susceptibility to dietary fat, Dev Biol 306: 584-598.
[15] Anini Y, Mayne J, Gagnon J, Sherbafi J, Chen A, Kaefer N, Chrétien M, Mbikay M. (2010) Genetic deficiency for proprotein convertase subtilisin/kexin type 2 in mice is associated with decreased adiposity and protection from dietary fat-induced body weight gain, Int J Obes 34: 1599-1607.
[16] Sirois F, Kaefer N, Currie KA, Chrétien M, Nkongolo KK, Mbikay M. (2012) Allelic clustering and ancestry-dependent frequencies of rs6232, rs6234, and rs6235 PCSK1 SNPs in a Northern Ontario population sample, J Community Genet 104: 682–687.
[17] Denis N, Palmer-Smith H, Elisma F, Busuttil A, Wright TG, Bou Khalil M, Prat A, Seidah NG, Chrétien M, Mayne J, Figeys D. (2011) Quantitative proteomic analysis of PCSK9 gain of function in human hepatic HuH7 cells, J Proteome Res 10: 2011-2026.