Abstract
Abstract
Introduction
Cardiovascular disease is the leading cause of death worldwide (Dagenais et al. 2020), and its main risk factor is LDL-C (Hagenbeek et al. 2020). Only a few genes are associated with LDL-C concentrations, and only 2 genes,
ANGPTL3
(Musunuru et al. 2010) and
LIPC
, are associated with familial combined hypocholesterolemia. Our team recently identified the second genetic cause associated with familial combined hypocholesterolemia, a gain-of-function mutant of the
LIPC
gene encoding hepatic lipase (HL),
LIPC
-E97G (Dijk et al. 2022). Although the mode of action of this variant remains largely unknown, we have demonstrated that it significantly increases the phospholipase activity of HL and affects lipoprotein metabolism by promoting plasma cholesterol clearance, particularly of LDL and HDL.
Objective
The aim of this study was to explore the additive effect of our HL-E97G variant with a pharmacological inhibitor of the ANGPTL3 protein, evinacumab, on cholesterolemia and atherosclerosis.
Materiel and methods
Atherosclerosis measurements were performed on
Ldlr
−/−
mice fed a pro-atherogenic diet. These mice received a single injection of a liver-targeting AAV8 expressing the wild-type or E97G human form of the
LIPC
gene (1×10
11
genome copies/mouse) and a weekly injection of NaCl or evinacumab (25 mg/kg/week).
Results
From a therapeutic approach, we demonstrated a cumulative effect of HL-E97G with evinacumab. Atherosclerotic lesions in the aortic arch of
Ldlr
−/−
mice were reduced by 36% (p=0.4897) with evinacumab, by 65% (p-value=0.0028) with HL-E97G, and by 80% (p-value
Conclusion
Our data demonstrate that HL-E97G reduces the development of atherosclerosis in mice in an LDLR- and ANGPTL3-independent manner, strongly reinforcing the therapeutic potential of HL-E97G for patients at high risk of cardiovascular disease.