Thesis defense Lucie Vince

Equipe

Team IV - Cardiometabolic diseases

Directeur de thèse 

Cédric Le May

Co-encadrant

Antoine Rimbert
 

Rapporteurs

Sophie Béliard, MD, PhD, PU-PH, AP-HM Marseille
Xavier Collet,PhD, DR, I2MC Toulouse

Examinateurs

Coralie Fontaine, PhD, DR, I2MC Toulouse 
Thomas Gautier, PhD, CR, CTM Dijon 

 

Abstract :

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death worldwide. Among the many risk factors, high levels of LDL cholesterol are a major determinant. Despite existing lipid-lowering therapies, a large number of patients do not achieve the LDL-cholesterol target necessary to protect them against cardiovascular risks. This is particularly true for patients with homozygous familial hypercholesterolemia (HoFH). The search for new genetic and therapeutic targets has enabled us to identify a rare gain-of-function variant in the LIPC gene encoding hepatic lipase (HL). This LIPC-E97G variant is the second leading genetic cause of combined familial hypocholesterolemia, characterized by very low concentrations of LDL and HDL cholesterol. During my Ph.D. training, we demonstrated that this variant exerts potent cholesterol-lowering and anti-atherogenic effects through a mechanism of action independent of the LDL receptor. Furthermore, we demonstrated in mice that this variant acts synergistically with one of the few drugs effective in patients with HoFH: ANGPTL3 inhibitors. Finally, we determined that long-term expression of the variant did not lead to metabolic disorders or pathophysiological complications. My doctoral research has thus helped to reinforce the therapeutic potential of this hepatic lipase variant in the management of patients with dyslipidemia and at risk for ASCVD.