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Liver-specific ?-catenin knockout mice have bile canalicular abnormalities, bile secretory defect, and intrahepatic cholestasis.

ABSTRACT: Beta-catenin plays important roles in liver physiology and hepatocarcinogenesis. While studying the role of ?-catenin in diet-induced steatohepatitis, we recently found that liver-specific ?-catenin knockout (KO) mice exhibit intrahepatic cholestasis. This study was undertaken to further characterize the role of ?-catenin in biliary physiology. KO mice and wild-type (WT) littermates were fed standard chow or a diet supplemented with 0.5% cholic acid for 2 weeks. Chow-fed KO mice had higher serum and hepatic total bile acid levels and lower bile flow rate than WT mice. Expression levels of bile acid biosynthetic genes were lower and levels of major bile acid exporters were similar, which therefore could not explain the KO phenotype. Despite loss of the tight junction protein claudin-2, KO mice had preserved functional integrity of tight junctions. KO mice had bile canalicular morphologic abnormalities as evidenced by staining for F-actin and zona occludens 1. Electron microscopy revealed dilated and tortuous bile canaliculi in KO livers along with decreased canalicular and sinusoidal microvilli. KO mice on a cholic acid diet had higher hepatic and serum bile acid levels, bile ductular reaction, increased pericellular fibrosis, and dilated, misshapen bile canaliculi. Compensatory changes in expression levels of several bile acid transporters and regulatory genes were found in KO livers.Liver-specific loss of ?-catenin leads to defective bile canalicular morphology, bile secretory defect, and intrahepatic cholestasis. Thus, our results establish a critical role for ?-catenin in biliary physiology.

SUBMITTER: Yeh TH

PROVIDER: S-EPMC2947599 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Liver-specific β-catenin knockout mice have bile canalicular abnormalities, bile secretory defect, and intrahepatic cholestasis.

Yeh Tzu-Hsuan TH Krauland Lindsay L Singh Vijay V Zou Baobo B Devaraj Prathab P Stolz Donna B DB Franks Jonathan J Monga Satdarshan P S SP Sasatomi Eizaburo E Behari Jaideep J

Hepatology (Baltimore, Md.) 20101001 4

<h4>Unlabelled</h4>Beta-catenin plays important roles in liver physiology and hepatocarcinogenesis. While studying the role of β-catenin in diet-induced steatohepatitis, we recently found that liver-specific β-catenin knockout (KO) mice exhibit intrahepatic cholestasis. This study was undertaken to further characterize the role of β-catenin in biliary physiology. KO mice and wild-type (WT) littermates were fed standard chow or a diet supplemented with 0.5% cholic acid for 2 weeks. Chow-fed KO mi ...[more]

PMID: 20722001

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Project description:β-Catenin, the downstream effector of the Wnt signaling, plays important roles in hepatic development, regeneration, and tumorigenesis. However, its role at hepatocyte adherens junctions (AJ) is relatively poorly understood, chiefly due to spontaneous compensation by γ-catenin. We simultaneously ablated β- and γ-catenin expression in mouse liver by interbreeding β-catenin-γ-catenin double-floxed mice and Alb-Cre transgenic mice. Double knockout mice show failure to thrive, impaired hepatocyte differentiation, cholemia, ductular reaction, progressive cholestasis, inflammation, fibrosis, and tumorigenesis, which was associated with deregulation of tight junctions (TJ) and bile acid transporters, leading to early morbidity and mortality, a phenotype reminiscent of progressive familial intrahepatic cholestasis (PFIC). To address the mechanism, we specifically and temporally eliminated both catenins from hepatocytes using adeno-associated virus 8 carrying Cre-recombinase under the thyroid-binding globulin promoter (AAV8-TBG-Cre). This led to a time-dependent breach of the blood-biliary barrier associated with sequential disruption of AJ and TJ verified by ultrastructural imaging and intravital microscopy, which revealed unique paracellular leaks around individual hepatocytes, allowing mixing of blood and bile and leakage of blood from one sinusoid to another. Molecular analysis identified sequential losses of E-cadherin, occludin, claudin-3, and claudin-5 due to enhanced proteasomal degradation, and of claudin-2, a β-catenin transcriptional target, which was also validated in vitro.ConclusionWe report partially redundant function of catenins at AJ in regulating TJ and contributing to the blood-biliary barrier. Furthermore, concomitant hepatic loss of β- and γ-catenin disrupts structural and functional integrity of AJ and TJ via transcriptional and posttranslational mechanisms. Mice with dual catenin loss develop progressive intrahepatic cholestasis, providing a unique model to study diseases such as PFIC. (Hepatology 2018;67:2320-2337).

Project description:BackgroundICP pregnant women have a unique profile of serum bile acid metabolism, thus the early and accurate identification of ICP patients is beneficial to early appropriate treatment and improvement of pregnancy outcomes. In this study, ultra-high performance liquid chromatography-mass spectrometry/mass spectrometry (UPLC-MS/MS) was used to analyze the 15 types of serum bile acid profiles among patients with ICP in third trimester, patients with cholelithiasis, and patients with hepatitis B virus. The ICP diagnostic model established by partial least squares-discriminant analysis (PLS-DA) was used to screen the differential bile acids for clinical subtypes of ICP. 144 cases of ICP patients were involved in this study, and divided into four subgroups according to serum level of TBA, DBIL, and ALT.Results(1) The differential serum bile acid profiles of ICP group and normal pregnant women were DCA, TDCA, TCA, GDCA and GLCA. (2) The differential serum bile acid profiles of the ICP1 group (ICP with jaundice) and normal pregnant women were TCDCA, TCA, GCA, GCDCA, TUDCA and GUDCA. (3) The differential serum bile acid profiles of the ICP3 group (Hyperchoicemia of pregnancy) and normal pregnant group was GUDCA, LCA, GLCA, UDCA, TUDCA, CDCA, and TLCA (P < 0.05). (4) The differential serum bile acid profiles of ICP4 group (idiopathic aminotransferase abnormality during pregnancy) and normal pregnant group was UDCA, GUDCA, TUDCA, GCA and GLCA (P < 0.05). (5) The occurrence of meconium-stained amniotic fluid, premature delivery and cesarean section in ICP1 group was significantly higher than normal group, ICP2 group, ICP3 group, and ICP4 group (P < 0.05); The occurrence of meconium-stained amniotic fluid, premature delivery and cesarean section in ICP2 group, ICP3 group, and ICP4 group was significantly higher than normal group (P < 0.05), but no difference was found among ICP2 group, ICP3 group, and ICP4 group (P > 0.05).ConclusionMaternal serum bile acid profiles are useful to differentiate the four subtypes of ICP. ICP with jaundice could be an important predictor of adverse pregnancy outcomes of ICP.

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Liver-specific ?-catenin knockout mice have bile canalicular abnormalities, bile secretory defect, and intrahepatic cholestasis.

Publications

Liver-specific β-catenin knockout mice have bile canalicular abnormalities, bile secretory defect, and intrahepatic cholestasis.

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