Targeting ApoC3 Paradoxically Aggravates Atherosclerosis in Hamsters With Severe Refractory Hypercholesterolemia

Abstract

RationaleApoC3 plays a central role in the hydrolysis process of triglyceride (TG)-rich lipoproteins mediated by lipoprotein lipase (LPL), which levels are positively associated with the incidence of cardiovascular disease (CVD). Although targeting ApoC3 by antisense oligonucleotide (ASO), Volanesorsen markedly reduces plasma TG level and increase high-density lipoprotein cholesterol (HDL-C) in patients with hypertriglyceridemia (HTG), the cholesterol-lowering effect of ApoC3 inhibition and then the consequential outcome of atherosclerotic cardiovascular disease (ASCVD) have not been reported in patients of familial hypercholesterolemia (FH) with severe refractory hypercholesterolemia yet.ObjectiveTo investigate the precise effects of depleting ApoC3 on refractory hypercholesterolemia and atherosclerosis, we crossed ApoC3-deficient hamsters with a background of LDLR deficiency to generate a double knockout (DKO) hamster model (LDLR−/−, XApoC3−/−, DKO).Approach and ResultsOn the standard laboratory diet, DKO hamsters had reduced levels of plasma TG and total cholesterol (TC) relative to LDLR−/− hamsters. However, upon high-cholesterol/high-fat (HCHF) diet feeding for 12 weeks, ApoC3 deficiency reduced TG level only in female animals without affecting refractory cholesterol in the circulation, whereas apolipoprotein A1 (ApoA1) levels were significantly increased in DKO hamsters with both genders. Unexpectedly, loss of ApoC3 paradoxically accelerated diet-induced atherosclerotic development in female and male LDLR−/− hamsters but ameliorated fatty liver in female animals. Further analysis of blood biological parameters revealed that lacking ApoC3 resulted in abnormal platelet (PLT) indices, which could potentially contribute to atherosclerosis in LDLR−/− hamsters.ConclusionsIn this study, our novel findings provide new insight into the application of ApoC3 inhibition for severe refractory hypercholesterolemia and ASCVD.

The associations between dietary flavonoid intake and hyperlipidemia: data from the national health and nutrition examination survey 2007–2010 and 2017–2018

“…This finding may be related to flavonoids being phytoestrogens, and there is a relationship between estrogen and lipid levels (59)(60)(61). Previous studies found that ApoC3 has a vital role in the lipoprotein lipase-mediated hydrolysis of triglyceride-rich lipoproteins, and knockdown of the ApoC3 gene significantly lowered triglyceride levels and elevated HDL cholesterol levels in hypertriglyceridemic patients (62). Estrogen inhibits ApoC3 expression, thereby reducing triglyceride levels (63).…”

Apolipoprotein C3: form begets function

“…1 ). The ability of APOC3 to prevent LPL’s action could explain why in a very hypertriglyceridemic LDLR-deficient hamster model, APOC3-deficiency, despite lowering plasma triglycerides, resulted in increased atherosclerosis ( 51 ); it is possible that increased LPL-mediated hydrolysis of TRL triglycerides brought about by APOC3-deficiency might have resulted in increased atherogenic remnant formation.…”

Applications of Genome Editing Technologies in CAD Research and Therapy with a Focus on Atherosclerosis

“…Under a high-cholesterol diet, these rabbits similarly exhibited reduced atherosclerosis as well as lower total cholesterol levels compared to wild-type rabbits [ 44 ]. Recent work from Xu et al on ApoC3 deficiency in LDLR-deficient hamsters suggests that loss of ApoC3 may paradoxically accelerate the atherosclerotic phenotype observed in LDLR-deficient hamsters on a high-cholesterol diet [ 129 ]. Further investigation on the effects and benefits of APOC3 inhibition in different animal models of atherosclerosis need to be carried out.…”