Department of Molecular Pathology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi, 409-3898, Japan.
Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, Ann Arbor, 48109, MI, USA.
Atherosclerosis. 2016 Feb;245:187-93. doi: 10.1016/j.atherosclerosis.2015.12.002. Epub 2015 Dec 9.
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.
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.
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.
兔子是研究高血脂和动脉粥样硬化的最佳动物模型之一。尽管已经创建了许多转基因兔，但由于缺乏兔胚胎干细胞，基因敲除（KO）兔的开发一直是不可能的。我们最近与其他人一起使用基因组编辑技术生成了 KO 兔。在当前的研究中，我们对 apoE KO 兔在正常饮食和胆固醇饮食下的脂蛋白谱进行了表征，并研究了它们对饮食诱导的动脉粥样硬化的易感性。
我们分析了 apoE KO 兔的血浆脂质和脂蛋白，并将其与野生型兔进行了比较。在正常饮食下，纯合子（而非杂合子）apoE KO 兔表现出轻度高脂血症，当用胆固醇饮食挑战时，它们比野生型兔更容易发生饮食诱导的高脂血症，并且它们的血浆总胆固醇水平显著升高（apoE KO 组为 1070 ± 61 mg/dL，野生型组为 169 ± 79 mg/dL，p < 0.001）。apoE KO 兔的高脂血症是由残粒脂蛋白升高引起的。有趣的是，apoE KO 兔中增加的残粒脂蛋白主要由 apoB-48 组成，并且富含 apoA-I 和 apoA-IV 。此外，当用胆固醇饮食喂养 10 周时，apoE KO 兔比野生型兔更容易发生主动脉粥样硬化。
据我们所知，这是首次报道用于研究脂质和脂蛋白代谢的 KO 兔的生成。apoE KO 兔应该是研究人类高脂血症和动脉粥样硬化的有用模型。
