Zebrafish abcb11b mutant reveals strategies to restore bile excretion impaired by bile salt export pump deficiency
Autor: | Daniel Leino, Alexander Miethke, Chunyue Yin, Jillian L. Ellis, John D. Schuetz, C. Alexander Valencia, Kevin E. Bove, Erin G. Schuetz |
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Rok vydání: | 2018 |
Předmět: |
Male
0301 basic medicine medicine.medical_specialty medicine.drug_class Mutant Cholestasis Intrahepatic Article 03 medical and health sciences 0302 clinical medicine Cholestasis Internal medicine Autophagy medicine Animals Bile Humans ATP Binding Cassette Transporter Subfamily B Member 1 ABCB11 Zebrafish ATP Binding Cassette Transporter Subfamily B Member 11 Sirolimus Hepatology biology Bile acid Progressive familial intrahepatic cholestasis Infant biology.organism_classification medicine.disease Bile Salt Export Pump Cell biology 030104 developmental biology Endocrinology medicine.anatomical_structure Liver 030220 oncology & carcinogenesis Hepatocyte Mutation Hepatocytes Female Immunosuppressive Agents |
Zdroj: | Hepatology. 67:1531-1545 |
ISSN: | 1527-3350 0270-9139 |
Popis: | 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.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. (Hepatology 2018;67:1531-1545). |
Databáze: | OpenAIRE |
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