Within the context of residual cardiovascular risk in post-
statin era, emerging evidence from epidemiologic and human genetic studies have demonstrated that triglyceride (TG)-rich lipoproteins and their remnants are causally related to cardiovascular risk. While, carriers of loss-of-function mutations of ApoC3 have low TG levels and are protected from
cardiovascular disease (CVD). Of translational significance, siRNAs/
antisense oligonucleotide (ASO) targeting ApoC3 is beneficial for patients with atherosclerotic CVD. Therefore, animal models of atherosclerosis with both hypercholesterolemia and
hypertriglyceridemia are important for the discovery of novel therapeutic strategies targeting TG-lowering on top of traditional
cholesterol-lowering. In this study, we constructed a novel mouse model of
familial combined hyperlipidemia through inserting a human ApoC3 transgene (hApoC3-Tg) into C57BL/6 J mice and injecting a gain-of-function variant of adeno-associated virus-
proprotein convertase subtilisin/kexin type 9 (AAV-PCSK9)-D377Y concurrently with high
cholesterol diet (HCD) feeding for 16 weeks. In the last 10 weeks, hApoC3-Tg mice were orally treated with a combination of
atorvastatin (10 mg·kg-1·d-1) and
fenofibrate (100 mg·kg-1·d-1). HCD-treated hApoC3-Tg mice demonstrated elevated levels of serum TG, total
cholesterol (TC) and
low density lipoprotein-cholesterol (
LDL-C).
Oral administration of
atorvastatin and
fenofibrate significantly decreased the plaque sizes of en face aorta, aortic sinus and innominate artery accompanied by improved
lipid profile and distribution. In summary, this novel mouse model is of considerable clinical relevance for evaluation of anti-atherosclerotic drugs by targeting both
hypercholesterolemia and
hypertriglyceridemia.