Manabu Niimi1, Dongshan Yang2, Shuji Kitajima3, Bo Ning1, Chuan Wang1, Shen Li1, Enqi Liu4, Jifeng Zhang2, Y Eugene Chen2, Jianglin Fan5. 1. Department of Molecular Pathology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi, 409-3898, Japan. 2. Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, Ann Arbor, 48109, MI, USA. 3. Division of Biological Resources and Development, Analytical Research Center for Experimental Sciences, Saga University, Saga, 840-8501, Japan. 4. Research Institute of Atherosclerotic Disease and Laboratory Animal Center, Xi'an Jiaotong University School of Medicine, Xi'an, 710061, China. 5. Department of Molecular Pathology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi, 409-3898, Japan; Department of Pathology, Xi'an Medical University, Xi'an, 710021, China. Electronic address: jianglin@yamanashi.ac.jp.
Abstract
OBJECTIVE: Rabbits are one of the best animal models for the study of hyperlipidemia and atherosclerosis. Although many transgenic rabbits have been created, the development of gene knockout (KO) rabbits has been impossible due to the lack of rabbit embryonic stem cells. We along with others recently generated KO rabbits using genome editing techniques. In the current study, we characterized the lipoprotein profiles of apoE KO rabbits on both chow and cholesterol diets and investigated their susceptibility to a diet-induced atherosclerosis. APPROACH AND RESULTS: We analyzed plasma lipids and lipoproteins of apoE KO rabbits and compared them with those of wild-type rabbits. On a chow diet, homozygous (but not heterozygous) apoE KO rabbits showed mild hyperlipidemia and, when challenged with a cholesterol diet, they showed greater susceptibility to diet-induced hyperlipidemia than did the wild-type rabbits and their plasma total cholesterol levels were remarkably increased (1070 ± 61 mg/dL in apoE KO vs. 169 ± 79 mg/dL in the wild type, p < 0.001). Hyperlipidemia in apoE KO rabbits was caused by elevated remnant lipoproteins. Interestingly, increased remnant lipoproteins in apoE KO rabbits were predominated by apoB-48 and rich in both apoA-I and apoA-IV contents. Furthermore, apoE KO rabbits developed greater aortic atherosclerosis than wild-type rabbits when fed with a cholesterol diet for 10 weeks. CONCLUSIONS: To our knowledge, this is the first report of generating KO rabbits for the study of lipid and lipoprotein metabolism. ApoE KO rabbits should be a useful model for the study of human hyperlipidemia and atherosclerosis.
OBJECTIVE:Rabbits are one of the best animal models for the study of hyperlipidemia and atherosclerosis. Although many transgenic rabbits have been created, the development of gene knockout (KO) rabbits has been impossible due to the lack of rabbit embryonic stem cells. We along with others recently generated KO rabbits using genome editing techniques. In the current study, we characterized the lipoprotein profiles of apoE KO rabbits on both chow and cholesterol diets and investigated their susceptibility to a diet-induced atherosclerosis. APPROACH AND RESULTS: We analyzed plasma lipids and lipoproteins of apoE KO rabbits and compared them with those of wild-type rabbits. On a chow diet, homozygous (but not heterozygous) apoE KO rabbits showed mild hyperlipidemia and, when challenged with a cholesterol diet, they showed greater susceptibility to diet-induced hyperlipidemia than did the wild-type rabbits and their plasma total cholesterol levels were remarkably increased (1070 ± 61 mg/dL in apoE KO vs. 169 ± 79 mg/dL in the wild type, p < 0.001). Hyperlipidemia in apoE KO rabbits was caused by elevated remnant lipoproteins. Interestingly, increased remnant lipoproteins in apoE KO rabbits were predominated by apoB-48 and rich in both apoA-I and apoA-IV contents. Furthermore, apoE KO rabbits developed greater aortic atherosclerosis than wild-type rabbits when fed with a cholesterol diet for 10 weeks. CONCLUSIONS: To our knowledge, this is the first report of generating KO rabbits for the study of lipid and lipoprotein metabolism. ApoE KO rabbits should be a useful model for the study of humanhyperlipidemia and atherosclerosis.