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.
Highlights
Elevated triglyceride (TG) levels caused by genetic or environmental factors are positively associated with the increased incidence of atherosclerotic cardiovascular disease (ASCVD) and acute pancreatitis (AP) [1]
Further analysis of blood biological parameters revealed that lacking apolipoprotein C3 (ApoC3) resulted in abnormal platelet (PLT) indices, which could potentially contribute to atherosclerosis in lowdensity lipoprotein receptor (LDLR)−/− hamsters
We found that ApoC3 deficiency did not accelerate obesity in double knockout (DKO) hamsters when compared to controls (Figure 1D)
Summary
Elevated triglyceride (TG) levels caused by genetic or environmental factors are positively associated with the increased incidence of atherosclerotic cardiovascular disease (ASCVD) and acute pancreatitis (AP) [1]. Unlike the contradictory data from the LPL activator, abrogating the inhibitory effects of ApoC3 and ANGPTLs on LPL activity consistently reduces circulating TG levels, yielding promising outcomes of dyslipidemia in different experimental animal models [4]. Evinacumab, an antibody that inhibits ANGPTL3 reduces TG level in circulation by enhancing LPL activity and significantly decreases low-density lipoprotein cholesterol (LDL-C) in patients with familial hypercholesterolemia (FH) in two independent phase 3 trials [5, 6]. Targeting ApoC3 by antisense oligonucleotide (ASO), volanesorsen, markedly reduces plasma TG level in patients with HTG [7, 8], the cholesterol-lowering effect of ApoC3 inhibition and the consequential outcomes
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