Zebrafish as a Model to Study Cholestatic Liver Diseases
Cholestasis is a condition that impairs bile flow, resulting in retention of bile fluid in the liver. It may cause significant morbidity and mortality due to pruritus, malnutrition, and complications from portal hypertension secondary to biliary cirrhosis
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troduction Cholestasis is a pathology defined by impaired bile flow due to defects in hepatocyte bile acid uptake, conjugation, or excretion (hepatocellular cholestasis), or biliary tract obstruction (obstructive cholestasis) (Fig. 1). Environmental factors, such as viral infection, toxic insults, and hormonal changes, account for 75% of the conditions that lead to cholestasis. Genetic disorders cause the remaining 25% cases [1]. If untreated, retention of bile acids in the liver and serum results in pruritus, which is often refractory to medical or surgical therapy. Biliary fibrosis frequently progresses to end-stage liver disease with portal hypertension and its life- threatening complications including ascites, infections, and catastrophic bleeding from esophageal varices. On the other hand, lack of luminal bile acids leads to fat malabsorption, malnutrition, and deficiency in the fat-soluble vitamins. In the past two decades, rodent models have provided in vivo tools to investigate the pathogenesis of cholestasis and test the Mathieu Vinken (ed.), Experimental Cholestasis Research, Methods in Molecular Biology, vol. 1981, https://doi.org/10.1007/978-1-4939-9420-5_18, © Springer Science+Business Media, LLC, part of Springer Nature 2019
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Duc-Hung Pham and Chunyue Yin
Fig. 1 Common causes of cholestatic liver diseases. Diseases that have been modeled in zebrafish are shown in black. PFIC progressive familial intrahepatic cholestasis, BRIC benign recurrent intrahepatic cholestasis, PSC primary sclerosing cholangitis, PBC primary biliary cholangitis
e fficacy of new treatment strategies [2]. However, no single mouse model can strictly reproduce all the features of human cholestatic liver diseases. Incorporating multiple animal models is necessary to gain complementary insights into the pathophysiology. The teleost zebrafish (Danio rerio) has emerged as a popular animal model for studying liver development and diseases. Its general strengths include rapid external development, transparent larvae, accessibility to genetic and chemical manipulations, inexpensive maintenance, and ease of collecting hundreds of embryos on a weekly base. Unlike mice, laboratory zebrafish strains are not inbred and its genetic background does not impose a significant impact on the phenotype. Zebrafish liver becomes functional by 4 days postfertilization and contains counterparts of mammalian liver cell types, despite some architectural differences (Fig. 2) [3]. Similar to mammals, zebrafish hepatocytes secrete bile salts through bile canaliculus on the apical side. Bile fluid is drained to a network of intrahepatic bile ducts that is connected to extrahepatic bile duct. Zebrafish has been used to model cholestatic liver diseases, including progressive familial intrahepatic cholestasis type 2 (PFIC2) [4], Alagille syndrome [5, 6], biliary atresia [7–13], arthrogryposis-renal dysfunction-cholestasis syndrome [14, 15], North American Indian childhood cirrhosis [16], and choledochal cysts [17]. Some of these zebrafish models overc
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