Spontaneous severe hypercholesterolemia and atherosclerosis lesions in rabbits with deficiency of low-density lipoprotein receptor (LDLR) on exon 7.
Spontaneous severe hypercholesterolemia and atherosclerosis lesions in rabbits with deficiency of low-density lipoprotein receptor (LDLR) on exon 7.
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外显子 7 低密度脂蛋白受体 (LDLR) 缺陷家兔自发性严重高胆固醇血症和动脉粥样硬化病变
DOI：
10.1016/j.ebiom.2018.09.020
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发表时间：
2018-10
期刊：
影响因子：
11.1
通讯作者：
Cheng Y
中科院分区：
文献类型：
--
作者：
Lu R;Yuan T;Wang Y;Zhang T;Yuan Y;Wu D;Zhou M;He Z;Lu Y;Chen Y;Fan J;Liang J;Cheng Y
Rabbits (Oryctolagus cuniculus) have been the very frequently used as animal models in the study of human lipid metabolism and atherosclerosis, because they have similar lipoprotein metabolism to humans. Most of hyperlipidemia and atherosclerosis rabbit models are produced by feeding rabbits a high-cholesterol diet. Gene editing or knockout (KO) offered another means of producing rabbit models for study of the metabolism of lipids and lipoproteins. Even so, apolipoprotein (Apo)E KO rabbits must be fed a high-cholesterol diet to induce hyperlipidemia. In this study, we used the CRISPR/Cas9 system anchored exon 7 of low-density lipoprotein receptor (LDLR) in an attempt to generate KO rabbits. We designed two sgRNA sequences located in E7:g.7055–7074 and E7:g.7102–7124 of rabbit LDLR gene, respectively. Seven LDLR-KO founder rabbits were generated, and all of them contained biallelic modifications. Various mutational LDLR amino acid sequences of the 7 founder rabbits were subjected to tertiary structure modeling with SWISS-MODEL, and results showed that the structure of EGF-A domain of each protein differs from the wild-type. All the founder rabbits spontaneously developed hypercholesterolemia and atherosclerosis on a normal chow (NC) diet. Analysis of their plasma lipids and lipoproteins at the age of 12 weeks revealed that all these KO rabbits exhibited markedly increased levels of plasma TC (the highest of which was 1013.15 mg/dl, 20-fold higher than wild-type rabbits), LDL-C (the highest of which was 730.00 mg/dl, 35-fold higher than wild-type rabbits) and TG accompanied by reduced HDL-C levels. Pathological examinations of a founder rabbit showed prominent aortic atherosclerosis lesions and coronary artery atherosclerosis.In conclusion, we have reported the generation LDLR-KO rabbit model for the study of spontaneous hypercholesterolemia and atherosclerosis on a NC diet. The LDLR-KO rabbits should be a useful rabbit model of human familial hypercholesterolemia (FH) for the simulations of human primary hypercholesterolemia and such models would allow more exact research into cardio-cerebrovascular disease.
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影响因子：
2.8
作者：
Waluś-Miarka M;Sanak M;Idzior-Waluś B;Miarka P;Witek P;Małecki MT;Czarnecka D
通讯作者：
Czarnecka D
影响因子：
15.9
作者：
ISHIBASHI, S;BROWN, MS;HERZ, J
通讯作者：
HERZ, J
影响因子：
56.9
作者：
BROWN, MS;GOLDSTEIN, JL
通讯作者：
GOLDSTEIN, JL
DOI：
10.1038/88556
发表时间：
2001-06-01
期刊：
NATURE STRUCTURAL BIOLOGY
影响因子：
--
作者：
Jeon, H;Meng, WY;Blacklow, SC
通讯作者：
Blacklow, SC
CRISPR-stat：一种简单可靠的基于PCR的方法，用于评估目标特异性SGRNA活性。
影响因子：
14.9
作者：
Carrington B;Varshney GK;Burgess SM;Sood R
通讯作者：
Sood R