Bodewes Frank A J A, Bijvelds Marcel J, de Vries Willemien, Baller Juul F W, Gouw Annette S H, de Jonge Hugo R, Verkade Henkjan J
Department of Pediatrics, University of Groningen, Beatrix Children's Hospital-University Medical Center, Groningen, The Netherlands.
Department of Gastroenterology & Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands.
PLoS One. 2015 Feb 13;10(2):e0117599. doi: 10.1371/journal.pone.0117599. eCollection 2015.
The cause of Cystic fibrosis liver disease (CFLD), is unknown. It is well recognized that hepatic exposure to hydrophobic bile salts is associated with the development of liver disease. For this reason, we hypothesize that, CFTR dependent variations, in the hepatic handling of hydrophobic bile salts, are related to the development CFLD. To test our hypothesis we studied, in Cftr-/- and control mice, bile production, bile composition and liver pathology, in normal feeding condition and during cholate exposure, either acute (intravenous) or chronic (three weeks via the diet). In Cftr-/- and control mice the basal bile production was comparable. Intravenous taurocholate increased bile production to the same extent in Cftr-/- and control mice. However, chronic cholate exposure increased the bile flow significantly less in Cftr-/- mice than in controls, together with significantly higher biliary bile salt concentration in Cftr-/- mice. Prolonged cholate exposure, however, did not induce CFLD like pathology in Cftr-/- mice. Chronic cholate exposure did induce a significant increase in liver mass in controls that was absent in Cftr-/- mice. Chronic cholate administration induces a cystic fibrosis-specific hepatobiliary phenotype, including changes in bile composition. These changes could not be associated with CFLD like pathological changes in CF mouse livers. However, chronic cholate administration induces liver growth in controls that is absent in Cftr-/- mice. Our findings point to an impaired adaptive homeotrophic liver response to prolonged hydrophobic bile salt exposure in CF conditions.
囊性纤维化肝病（CFLD）的病因尚不清楚。人们已经充分认识到肝脏暴露于疏水性胆汁盐与肝病的发展有关。因此，我们假设，CFTR依赖性的疏水性胆汁盐肝脏处理变化与CFLD的发展有关。为了验证我们的假设，我们在正常喂养条件下以及在急性（静脉注射）或慢性（通过饮食三周）胆酸盐暴露期间，研究了Cftr-/-小鼠和对照小鼠的胆汁生成、胆汁成分和肝脏病理学。在Cftr-/-小鼠和对照小鼠中，基础胆汁生成相当。静脉注射牛磺胆酸盐在Cftr-/-小鼠和对照小鼠中使胆汁生成增加到相同程度。然而，慢性胆酸盐暴露使Cftr-/-小鼠的胆汁流量增加明显少于对照小鼠，同时Cftr-/-小鼠的胆汁盐浓度明显更高。然而，长期胆酸盐暴露并未在Cftr-/-小鼠中诱导出类似CFLD的病理学变化。慢性胆酸盐暴露确实在对照小鼠中诱导了肝脏重量的显著增加，而在Cftr-/-小鼠中则没有。慢性胆酸盐给药诱导了一种囊性纤维化特异性的肝胆表型，包括胆汁成分的变化。这些变化与CF小鼠肝脏中类似CFLD的病理变化无关。然而，慢性胆酸盐给药在对照小鼠中诱导了肝脏生长，而在Cftr-/-小鼠中则没有。我们的研究结果表明，在CF条件下，肝脏对长期疏水性胆汁盐暴露的适应性同态调节反应受损。
