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.