胆盐出口泵
胆汁淤积
斑马鱼
进行性家族性肝内胆汁淤积症
生物
多药耐药蛋白2
突变体
胆汁酸
ATP结合盒运输机
生物化学
内科学
内分泌学
运输机
医学
基因
肝移植
移植
作者
Jillian L. Ellis,Kevin E. Bove,Erin G. Schuetz,Daniel Leino,C. Alexander Valencia,John D. Schuetz,Alexander Miethke,Chunyue Yin
出处
期刊:Hepatology
[Wiley]
日期:2018-02-23
卷期号:67 (4): 1531-1545
被引量:34
摘要
Bile salt export pump (BSEP) adenosine triphosphate–binding cassette B11 (ABCB11) is a liver‐specific ABC transporter that mediates canalicular bile salt excretion from hepatocytes. Human mutations in ABCB11 cause progressive familial intrahepatic cholestasis type 2. Although over 150 ABCB11 variants have been reported, our understanding of their biological consequences is limited by the lack of an experimental model that recapitulates the patient phenotypes. We applied CRISPR/Cas9‐based genome editing technology to knock out abcb11b , the ortholog of human ABCB11 , in zebrafish and found that these mutants died prematurely. Histological and ultrastructural analyses showed that abcb11b mutant zebrafish exhibited hepatocyte injury similar to that seen in patients with progressive familial intrahepatic cholestasis type 2. Hepatocytes of mutant zebrafish failed to excrete the fluorescently tagged bile acid that is a substrate of human BSEP. Multidrug resistance protein 1, which is thought to play a compensatory role in Abcb11 knockout mice, was mislocalized to the hepatocyte cytoplasm in abcb11b mutant zebrafish and in a patient lacking BSEP protein due to nonsense mutations in ABCB11 . We discovered that BSEP deficiency induced autophagy in both human and zebrafish hepatocytes. Treatment with rapamycin restored bile acid excretion, attenuated hepatocyte damage, and extended the life span of abcb11b mutant zebrafish, correlating with the recovery of canalicular multidrug resistance protein 1 localization. Conclusions: Collectively, these data suggest a model that rapamycin rescues BSEP‐deficient phenotypes by prompting alternative transporters to excrete bile salts; multidrug resistance protein 1 is a candidate for such an alternative transporter. (H epatology 2018;67:1531‐1545).
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