HEPALIPA

Despite the emergence of innovative therapeutic solutions in recent years, there is still a need for further research on strategies to reduce plasma low-density lipoprotein cholesterol levels, as a significant proportion of patients do not achieve their cholesterol reduction goals and remain at risk of developing atherosclerotic cardiovascular disease. Recently, we characterized the second genetic cause of familial combined hypocholesterolemia by discovering a gain of function mutation in the LIPC gene encoding for hepatic lipase. This LIPC-E97G variant alters the structural conformation of the enzyme and strongly increases its phospholipase activity. Interestingly, its ectopic expression in humanized APOE*3.Leiden.CETP mice mimics the human lipid phenotype and leads to a rapid and sustainable reduction of plasma phospholipids, triglycerides and cholesterol levels. The three main objectives of this proposal are: 1) To identify & characterize new LIPC variants in cohorts of patients with undefined origin of extremely low plasma cholesterol levels 2) To understand the mode of action & pathways involved in the lipid lowering effects of LIPC E97G 3) To evaluating the pro- or anti-atherogenic properties of E97G LIPC variant in human and mice Further deciphering the mechanism of action of E97C LIPC variant is of critical importance because: 1) this allows the characterization of a new LDL receptor-independent lipoprotein catabolism pathway; 2) this highlights the importance of the under-explored phospholipase activity in lipoprotein homeostasis; 3) this opens up a new therapeutic target for the treatment of severe hypercholesterolemia.