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发布日期:2018-09-26浏览次数:字号:[ ]


  -Press ReleaseA new animal model for hypercholesterolemia research

    近日,扬州大学兽医学院和江苏省动物重要疫病与人兽共患病防控协同创新中心成勇教授、扬州大学转化医学研究院梁景岩教授、日本山梨大学医学院范江霖教授为通讯作者,扬州大学兽医学院和江苏省动物重要疫病与人兽共患病防控协同创新中心博士研究生陆睿、扬州大学转化医学研究院袁婷婷、王英歌为并列第一作者,联合在Lancet子刊EBioMedicine发表题为“Spontaneous severe hypercholesterolemia and atherosclerosis lesions in rabbits with deficiency of low-density lipoprotein receptor (LDLR) on exon 7” 的研究长文(Research Article),为家族性高胆固醇血症的研究与治疗提供了崭新的疾病动物模型。



    受该杂志推荐,特发此新闻公告(Press release)。

    家族性高胆固醇血症(Familial hypercholesterolemia)是人类最常见的遗传性疾病之一。其特征是出生时低密度脂蛋白胆固醇(LDL-C)异常升高,如不及时治疗会导致过早的动脉粥样硬化、心血管疾病(CVD)发生,且致死年龄较低。多数情况下,这种疾病都是由位于常染体上的低密度脂蛋白受体(LDLR)基因突变引起的。







 Press release

A new animal model for hypercholesterolemia research

(Rabbits with deficiency of LDLR)

Researchers from College of Veterinary Medicine and Medical College, Yangzhou University and Faculty of Medicine, University of Yamanashi established a new animal model for studying familial hypercholesterolemia (FH). The team established rabbits with deficiency of low-density lipoprotein receptor (LDLR) on exon 7 using Crispr/Cas9. The rabbits spontaneously developed severe hypercholesterolemia and atherosclerosis lesions on normal chow diet. The work has been published online in the international scientific journal EbioMedicine(2018.09.19).

About familial hypercholesterolemia

Familial hypercholesterolaemia is one of the most common inherited metabolic diseases in humans and can affect individuals from all ethnic groups. When left untreated, this genetic disorder of cholesterol metabolism can lead to premature atherosclerosis, cardiovascular disease (CVD) and often death at a very young age. The low-density lipoprotein receptor (LDLR) plays a key role in the regulation of cholesterol homeostasis. When the LDLR is defective, low-density lipoprotein (LDL) cannot enter cells by receptor-mediated endocytosis and the lipoprotein accumulates in plasma, eventually producing atherosclerosis.

Study method and findings

The team established rabbits with deficiency of low-density lipoprotein receptor (LDLR) on exon 7 using Crispr/Cas9. The genomic DNA sequences, theoretical amino acid sequences, and tertiary structure of the LDLR knockout alleles were analyzed. Mutations can be divided into two groups: frame-shift mutation and deletion/insertion, both of which resulted in reduced content of functional LDLR on the cell surface and lost the ability to eliminate LDL-C. As expected, on a NC diet, all the LDLR-KO rabbits showed hyperlipidemia and their plasma TC and LDL-C levels were significantly higher than those of wild-type rabbits. The team sacrificed three LDLR-KO founder rabbits maintained on a NC diet and all of them showed different degrees of aortic lesions (red areas stained with Sudan IV). Micrographs of aortic atherosclerosis lesions indicated typical fibrous plaques contained rich foam cells derived from macrophages, depositions of calcium and covered by thin fibrous caps. The team also checked coronary artery of the most severe rabbit and found advanced coronary artery atherosclerosis.

Research implications

The LDLR-KO rabbits with biallelic mutations via the CRISPR/Cas9 system anchored exon 7 spontaneously developed severe hypercholesterolemia and atherosclerosis on a normal chow (NC) diet. During the past two decades, LDLR-KO mice have been widely used for studying many facets of lipid metabolism and atherosclerosis. However, homozygous LDL receptor KO mice on a chow diet, TC levels have been found to be only mildly elevated (200–300 mg/dl) and developed no or only mild atherosclerosis.

There is currently only one strain of spontaneous endogenous hypercholesterolemia rabbit, the Watanabe heritable hyperlipidemic (WHHL) strain. However, more than 1700 human LDLR mutations have been reported worldwide. Limited hyperlipidemic rabbit models hamper the investigation of all these mutations, since the rabbits have features of lipoprotein metabolism more similar to those of humans than mouse. We can expect that the LDLR-KO rabbit model will provide new insights into the understanding of FH and atherosclerosis and expand the power of the rabbit model for translational research in cardiovascular disease.


    This work was supported by the National Key Research and Development Program of China, the National Natural Science Foundation of China, the Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions, Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, and Technology, Japan.

Research Contact

Yangzhou University:

Yong Cheng (chengyong@yzu.edu.cn)

Jingyan Liang (jyliang@yzu.edu.cn);

University of Yamanashi:

Jianglin Fan (jianglin@yamanashi.ac.jp)

Journal article

Spontaneous severe hypercholesterolemia and atherosclerosis lesions in rabbits with deficiency of low-density lipoprotein receptor (LDLR) on exon 7

Full article link:



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