Haizhao Yan, Japan
University of Yamanashi Department of Molecular PathologyPresenter of 1 Presentation
Deletion of the apoCIII gene in knockout rabbits attenuates cholesterol diet-induced hyperlipidemia and protects against atherosclerosis
Abstract
Background and Aims
To investigate the pathophysiological functions of apolipoprotein CIII (apoCIII) in lipoprotein metabolism and atherosclerosis along with possible molecular mechanisms.
Methods
We used apoCIII knockout (KO) rabbits generated by zinc finger nuclease technique and compared the plasma lipids and their susceptibility to a cholesterol diet-induced atherosclerosis with wild-type (WT) rabbits.
Results
On a normal chow diet, apoCIII KO rabbits exhibited lower plasma levels of TG (up to 36% reduction) than WT rabbits while total cholesterol (TC) and HDL-cholesterol levels were unchanged. Analysis of lipoproteins isolated by sequential gradient ultracentrifugation revealed that reduced plasma TG levels in KO rabbits were accompanied by 73% reduction of very low-density lipoproteins (VLDLs) and 57% reduction of intermediate-density lipoproteins (IDLs). Furthermore, KO rabbits showed faster clearance rate of intralipid emulsion than WT rabbits. On a cholesterol-rich diet, KO rabbits exhibited constantly lower plasma TC and TG levels than WT rabbits, owing to a remarkable reduction of β-VLDLs, IDLs and LDLs. Aortic atherosclerosis areas were significantly reduced in KO rabbits compared with WT rabbits. Using DiI-labeled β-VLDLs, we found that deletion of apoCIII in β-VLDLs of KO rabbits enhances their uptake by cultured hepatocytes in vitro and exhibited faster clearance in vivo than β-VLDLs of WT rabbits.
Conclusions
These results indicate that apoCIII deficiency facilitates TG-rich lipoprotein catabolism and protects against cholesterol diet-induced atherosclerosis in KO rabbits. Therapeutic inhibition of apoCIII expression may become a novel means for the treatment of hyperlipidemia and atherosclerosis.