A transgenic zebrafish model of hepatocyte function in human Z α1-antitrypsin deficiency

被引:2
作者
Yip, Evelyn [1 ]
Giousoh, Aminah [1 ]
Fung, Connie [1 ]
Wilding, Brendan [1 ]
Prakash, Monica D. [1 ]
Williams, Caitlin [2 ]
Verkade, Heather [3 ]
Bryson-Richardson, Robert J. [2 ]
Bird, Phillip I. [1 ]
机构
[1] Monash Univ, Biomed Discovery Inst, Dept Biochem & Mol Biol, Melbourne, Vic 3800, Australia
[2] Monash Univ, Sch Biol Sci, Melbourne, Vic 3800, Australia
[3] Univ Melbourne, Dept Biochem & Mol Biol, Parkville, Vic 3052, Australia
基金
英国医学研究理事会;
关键词
alpha(1)-antitrypsin deficiency; Danio rerio; liver; serpin; SERPINA1; LIVER-DISEASE; MOUSE MODEL; ALPHA(1)-ANTITRYPSIN DEFICIENCY; GENE-EXPRESSION; ACCUMULATION; TRANSPOSON; HEPATITIS; MECHANISM; PATHOLOGY; CIRRHOSIS;
D O I
10.1515/hsz-2018-0391
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
In human alpha 1-antitrypsin deficiency, homozygous carriers of the Z (E324K) mutation in the gene SERPINA1 have insufficient circulating alpha 1-antitrypsin and are predisposed to emphysema. Misfolding and accumulation of the mutant protein in hepatocytes also causes endoplasmic reticulum stress and underpins long-term liver damage. Here, we describe transgenic zebrafish (Danio rerio) expressing the wildtype or the Z mutant form of human alpha 1-antitrypsin in hepatocytes. As observed in afflicted humans, and in rodent models, about 80% less alpha 1-antitrypsin is evident in the circulation of zebrafish expressing the Z mutant. Although these zebrafish also show signs of liver stress, they do not accumulate alpha 1-antitrypsin in hepatocytes. This new zebrafish model will provide useful insights into understanding and treatment of alpha 1-antitrypsin deficiency.
引用
收藏
页码:1603 / 1616
页数:14
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