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MCGILL UNIVERSITY A study of the Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) in glucose and insulin homeostasis by Julie Cruanès Supervisor: Dr. Nabil G. Seidah Department of Medicine Division of Experimental Medicine McGill University Montreal, Canada December 2020 A thesis submitted to McGill University in partial fulfillment of the requirements of the degree of Doctor of Philosophy © Julie Cruanès 2020 Abstract Atherosclerotic cardiovascular disease (ASCVD) is thought to account for >30% of all deaths today. Patients at very high risk, who suffer from ASCVD and comorbidities, such as diabetes, are projected to have 10-year event risks between 26% to 43%. Considering that low- density lipoprotein cholesterol (LDLc) is the main driver of ASCVD and that reducing its circulating levels was demonstrated to be beneficial in reducing clinical events, new guidelines required patients to reduce their LDLc levels to very low levels. Therefore, therapeutic agents are currently being developed in order to decrease this societal predicament. One of the very promising agents is directed towards lowering proprotein convertase subtilisin/kexin type 9 (PCSK9) synthesis or circulating levels. Indeed, clinical trials on these PCSK9-inhibitors demonstrated safety and beneficial effects on cardiovascular outcomes. Several research groups are interested in determining whether PCSK9 may be important for other processes than cholesterol homeostasis. Indeed, some groups propose that PCSK9 could play a role in the development of diabetic dyslipidemia. Other groups are concerned over the possibility that targeting PCSK9 could lead to the excessive ectopic accumulation of cholesterol and lipid particles in insulin sensitive tissues, resulting in lipotoxicity, insulin resistance and/or impaired insulin secretion. Therefore, we addressed these questions in this thesis. In the first section we investigated the possible direct effect that PCSK9 could have on the function and biosynthesis of the insulin receptor in cell culture and in mouse liver. In the second section we investigated whether the absence of PCSK9 in mice could lead to impaired glucose and insulin homeostasis. Our main results demonstrate that exogenous PCSK9 decreases insulin receptor signaling and in vitro expression leads to decreased biosynthesis likely due to upregulation of acute endoplasmic reticulum (ER) stress. Analyses of pancreatic β- cells and hepatocytes further demonstrated that the absence of PCSK9 in 6-month old male mice does not lead to impaired glucose or insulin homeostasis. Our studies provide a new mechanism for the potential role of PCSK9 in lipid homeostasis, suggesting that by decreasing insulin signaling, PCSK9 could promote the development of dyslipidemia, although further investigations are required to validate this hypothesis. Our analysis suggests that targeting PCSK9 in diabetic or pre-diabetic patients would be safe and could even be beneficial, keeping in mind, however, the limitations of our studies which are based on mouse models that inherently have low levels of LDLc. i Résumé La maladie cardiovasculaire athéroscléreuse (ASCVD) représenterait plus de 30% de tous les décès aujourd'hui. Les patients à très haut risque, qui souffrent d'ASCVD et de comorbidités, telles que le diabète, devraient présenter des risques d'événements sur 10 ans entre 26% et 43%. Considérant que le cholestérol à lipoprotéines de basse densité (LDLc) est le principal moteur de l'ASCVD et que la réduction de ses taux circulants s'est avérée bénéfique pour réduire les évènements cliniques, de nouvelles lignes directrices ont exigé des patients qu'ils réduisent leurs taux de LDLc à des niveaux très bas. Par conséquent, des agents thérapeutiques sont actuellement en cours de développement afin de réduire cette situation difficile pour la société. L'un des agents très prometteurs vise à abaisser la synthèse de la proprotéine convertase subtilisine / kexine de type 9 (PCSK9) ou les taux circulants. En effet, les essais cliniques sur ces inhibiteurs de la PCSK9 ont démontré leur innocuité et leurs effets bénéfiques sur les résultats cardiovasculaires. Plusieurs groupes de recherche sont intéressés à déterminer si la PCSK9 peut être importante pour d'autres processus que l'homéostasie du cholestérol. En effet, certains groupes proposent que la PCSK9 pourrait jouer un rôle dans le développement de la dyslipidémie diabétique. D'autres groupes s'inquiètent de la possibilité que le ciblage de la PCSK9 puisse entraîner une accumulation ectopique excessive de cholestérol et de particules lipidiques dans les tissus sensibles à l'insuline, entraînant une lipotoxicité, une résistance à l'insuline et / ou une altération de la sécrétion d'insuline. Par conséquent, nous avons abordé ces questions dans cette thèse. Dans la première section, nous avons étudié l’effet direct que la PCSK9 pourrait avoir sur la fonction et la biosynthèse du récepteur de l'insuline en culture cellulaire et dans le foie de la souris. Dans la deuxième section, nous avons examiné si l'absence de PCSK9 chez la souris pouvait entraîner une altération de l'homéostasie du glucose et de l'insuline. Nos principaux résultats démontrent que la PCSK9 exogène diminue la signalisation des récepteurs de l'insuline et que l'expression in vitro conduit à une diminution de la biosynthèse probablement due à une augmentation du stress du réticulum endoplasmique aigu. L'analyse des cellules β pancréatiques et des hépatocytes a en outre démontré que l’absence de la PCSK9 dans les souris mâles âgées de 6 mois n’altère pas homéostasie du glucose ou de l'insuline. Nos études fournissent un nouveau mécanisme pour le rôle potentiel de la PCSK9 dans l'homéostasie lipidique, suggérant qu'en diminuant la signalisation de l'insuline, PCSK9 pourrait favoriser le développement de la dyslipidémie, bien que des ii investigations supplémentaires soient nécessaires pour valider cette hypothèse. Pour conclure, notre analyse suggère que le ciblage de PCSK9 chez les patients diabétiques ou pré-diabétiques serait sûr et pourrait même être bénéfique, en gardant à l'esprit, cependant, les limites de nos études qui sont basées sur des modèles murins qui ont intrinsèquement de faibles niveaux de LDLc. iii Acknowledgements I would like to thank Dr. Nabil G. Seidah for giving me the truly exceptional opportunity to do research in his laboratory. Working with Dr. Seidah has taught me to be optimistic, perseverant and enthusiastic about science. This experience has led me to work alongside wonderful people everyday, learn and grow from challenges and failures and travel abroad to meet scientists from around the world, several of which have become close friends. I would also like to thank Dr. Annik Prat for being a strong example of a critical scientist, with immense care for excellent quality science. Annik and Nabil have proven to be essential pillars for this long journey through the thesis and I thank them for being there for me. I’d like to thank all the committee members as they have shown inestimable help and support throughout these years, Dr. Robert Kiss, Dr. Robert Day, Dr. Jennifer Estall, Dr. Vincent Poitout and Dr. Javier Di Noia. I thank all the Seidah lab members, present and past, for always lending an ear, a hand or a pipette. Perhaps I’d like to firstly thank those that have shown me how to work in the lab (from the first to the last day), Dr. Anna Roubstova Stepanova, Ann Chamberland, Marie-Claude Asselin, Josée Hamelin, Jadwiga Marcinkiewicz; those that have supported my always pressant requests, Dr. Delia Susan-Resiga, Alexandra Evagelidis and Ann (again). Then I’d like to thank the others that I have incessantly bugged with either scientific or even completely unrelated questions and conversations, Stephanie Duval, Ursula Andreo, Emmanuelle Girard, Sepideh and Sahar Mikaeeli, Yahya Ashraf, Loreleï Durand, Vatsal Sachan, Ali Ben Djoudi Ouadda, Elodie Weider, Valérie Menier, Chutikarn Butkinaree (Pui), Rashid Essalmani, Mouna Derbali and Priyanka Prabhala. Finally, I’d like to thank Brigitte Mary for making everything possible. I’d also like to thank my other dear IRCM fellows and friends, including Shiva Safavi and Sahar Bagherzadeh Yazdchi, Omar Al Rifai, Mélissa Léveillé and Nathalie Jouvet, Julie Lacombe and Monica Pata, Almira Kurbegovic, Marie Mutabaruka, Andreea Milasan and many others which I cannot list here. Last but not least, I’d like to thank my friends from outside the IRCM and my family; my dear and loving husband and daughter who have been very patient and understanding throughout these years. iv Table of contents Abstract ........................................................................................................................................... i Résumé ........................................................................................................................................... ii Acknowledgements ...................................................................................................................... iv Table of contents ........................................................................................................................... v List of tables.................................................................................................................................. ix List of figures ................................................................................................................................. x List of abbreviations ..................................................................................................................
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