Haizhao Yan1,2, Manabu Niimi1, Fumikazu Matsuhisa3, Huanjin Zhou1, Shuji Kitajima3, Yajie Chen1, Chuan Wang1, Xiawen Yang4, Jian Yao4, Dongshan Yang5, Jifeng Zhang5, Masami Murakami6, Katsuyuki Nakajima6, Yao Wang7, Enqi Liu8, Jingyan Liang9, Y Eugene Chen5, Jianglin Fan1,7. 1. From the Department of Molecular Pathology, Faculty of Medicine, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Chuo, Japan (H.Y., M.N., H.Z., Y.C., C.W., J.F.). 2. CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, China (H.Y.). 3. Division of Biological Science and Development, Analytical Research Center for Experimental Sciences, Saga University, Japan (F.M., S.K.). 4. Division of Molecular Signaling, Department of the Advanced Biomedical Research, Faculty of Medicine, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Chuo, Japan (X.Y., J.Y.). 5. Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, Ann Arbor (D.Y., J.Z., Y.E.C.). 6. Department of Clinical Laboratory Medicine, Gunma University, Graduate School of Medicine, Maebashi, Japan (M.M., K.N.). 7. School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, China (Y.W., J.F.). 8. Research Institute of Atherosclerotic Disease and Laboratory Animal Center, Xi'an Jiaotong University School of Medicine, China (E.L.). 9. Institute of Translational Medicine, Medical College, Yangzhou University, China (J.L.).
Abstract
OBJECTIVE: Apo (apolipoprotein) CIII mediates the metabolism of triglyceride (TG)-rich lipoproteins. High levels of plasma apoCIII are positively correlated with the plasma TG levels and increase the cardiovascular risk. However, whether apoCIII is directly involved in the development of atherosclerosis has not been fully elucidated. Approach and Results: To examine the possible roles of apoCIII in lipoprotein metabolism and atherosclerosis, we generated apoCIII KO (knockout) rabbits using ZFN (zinc finger nuclease) technique. On a normal standard diet, apoCIII KO rabbits exhibited significantly lower plasma levels of TG than those of WT (wild type) rabbits while total cholesterol and HDL (high-density lipoprotein) cholesterol levels were unchanged. Analysis of lipoproteins isolated by sequential ultracentrifugation revealed that reduced plasma TG levels in KO rabbits were accompanied by prominent reduction of VLDLs (very-low-density lipoproteins) and IDLs (intermediate-density lipoproteins). In addition, KO rabbits showed faster TG clearance rate after intravenous fat load than WT rabbits. On a cholesterol-rich diet, KO rabbits exhibited constantly and significantly lower levels of plasma total cholesterol and TG than WT rabbits, which was caused by a remarkable reduction of β-VLDLs-the major atherogenic lipoproteins. β-VLDLs of KO rabbits showed higher uptake by cultured hepatocytes and were cleared faster from the circulation than β-VLDLs isolated from WT rabbits. Both aortic and coronary atherosclerosis was significantly reduced in KO rabbits compared with WT rabbits. CONCLUSIONS: These results indicate that apoCIII deficiency facilitates TG-rich lipoprotein catabolism, and therapeutic inhibition of apoCIII expression may become a novel means not only for the treatment of hyperlipidemia but also for atherosclerosis.
OBJECTIVE:Apo (apolipoprotein) CIII mediates the metabolism of triglyceride (TG)-rich lipoproteins. High levels of plasma apoCIII are positively correlated with the plasma TG levels and increase the cardiovascular risk. However, whether apoCIII is directly involved in the development of atherosclerosis has not been fully elucidated. Approach and Results: To examine the possible roles of apoCIII in lipoprotein metabolism and atherosclerosis, we generated apoCIIIKO (knockout) rabbits using ZFN (zinc finger nuclease) technique. On a normal standard diet, apoCIIIKOrabbits exhibited significantly lower plasma levels of TG than those of WT (wild type) rabbits while total cholesterol and HDL (high-density lipoprotein) cholesterol levels were unchanged. Analysis of lipoproteins isolated by sequential ultracentrifugation revealed that reduced plasma TG levels in KOrabbits were accompanied by prominent reduction of VLDLs (very-low-density lipoproteins) and IDLs (intermediate-density lipoproteins). In addition, KOrabbits showed faster TG clearance rate after intravenous fat load than WT rabbits. On a cholesterol-rich diet, KOrabbits exhibited constantly and significantly lower levels of plasma total cholesterol and TG than WT rabbits, which was caused by a remarkable reduction of β-VLDLs-the major atherogenic lipoproteins. β-VLDLs of KOrabbits showed higher uptake by cultured hepatocytes and were cleared faster from the circulation than β-VLDLs isolated from WT rabbits. Both aortic and coronary atherosclerosis was significantly reduced in KOrabbits compared with WT rabbits. CONCLUSIONS: These results indicate that apoCIII deficiency facilitates TG-rich lipoprotein catabolism, and therapeutic inhibition of apoCIII expression may become a novel means not only for the treatment of hyperlipidemia but also for atherosclerosis.
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