Thesis defense Thibaud Sotin
https://umr1087.ppksup.univ-nantes.fr/medias/photo/sotin-thibaud-1-_1713859544131-jpg
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Le 08 July 2024Amphithéâtre V. Ferré (Bias 400),
Faculté de pharmacie, 9 rue Biasfalse false -
14h
Title of the thesis : Metabolic and functionnal consequences of total, hepatocyte or intestinal LDL receptor deficiency in mice
Equipe
Team IV - Cardiometabolic diseases
Directeur de thèse
Co-directeur
Cédric Le May
Co-encadrante
Rapporteurs
Catherine POSTIC, PhD, Université Paris Cité - Institut Cochin - Inserm U1016 / CNRS UMR 8104
Laurent YVANT-CHARVET, PhD, Université Côte d’Azur - C3M - Inserm UMR 1065
Examinateurs
Maryse GUERIN, PhD, Sorbonne Université - ICAN - UMRS Inserm 1166 / IHU ICANPhilippe MOULIN, MD, PhD, Université Lyon 1 - CarMeN – Inserm U1060 / INRAE U1397
Abstract
| Cardiovascular diseases remain the leading cause of mortality worldwide. Among the associated risk factors, hypercholesterolemia, characterized by elevated plasma low-density lipoprotein (LDL) concentrations, is the most prevalent. Mutations in the LDL receptor (LDLR) gene are a major cause of familial hypercholesterolemia, highlighting the crucial role of this protein in cholesterol homeostasis. However, current preclinical studies primarily rely on a mouse model that is completely deficient in Ldlr, thus overlooking the tissue-specific actions of this protein. In my doctoral research, I compared the effects of total, hepatocyte, and intestinal LDLR deficiency in mice across various metabolic contexts, on lipid homeostasis, the onset of atherosclerosis, and the progression of metabolic steatohepatitis (MASH). This work revealed new intestinal functions of LDLR and identified a significant role of extra-hepatocyte LDLR in the regulation of circulating lipids and the progression of MASH. Beyond LDLR, it is necessary to identify and characterize new hypocholesterolemic pathways. My host team has recently identified a LIPC gene variant, encoding for hepatic lipase, as a novel cause of familial combined hypocholesterolemia. Using the whole-body LDLR deficient mouse model of atherosclerosis developed during my thesis, I have demonstrated a hypocholesterolemic and anti-atherogenic effect of this variant, independently of LDLR, thus opening up new therapeutic perspectives for the management of cardiovascular diseases. |
Mis à jour le 03 June 2024.