title: Liver-specific β-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 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 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.
  
  
  CONCLUSIONS
  Liver-specific loss of β-catenin leads to defective bile canalicular morphology, bile secretory defect, and intrahepatic cholestasis. Thus, our results establish a critical role for β-catenin in biliary physiology.
authors: Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors: Tzu-Hsuan
authors: TH
authors: Yeh
authors: Lindsay
authors: L
authors: Krauland
authors: Vijay
authors: V
authors: Singh
authors: Baobo
authors: B
authors: Zou
authors: Prathab
authors: P
authors: Devaraj
authors: Donna B
authors: DB
authors: Stolz
authors: Jonathan
authors: J
authors: Franks
authors: Satdarshan P S
authors: SP
authors: Monga
authors: Eizaburo
authors: E
authors: Sasatomi
authors: Jaideep
authors: J
authors: Behari
mesh_terms: D000818:Animals; D001646:Bile / Q000378:metabolism; D001647:Bile Acids and Salts / Q000097:blood / Q000378:metabolism*; D001648:Bile Canaliculi / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002780:Cholestasis, Intrahepatic / Q000378:metabolism*; D019826:Cholic Acid / Q000494:pharmacology; D004032:Diet; D005260:Female; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051176:beta Catenin / Q000172:deficiency*
chemical_list: D001647:Bile Acids and Salts; D051176:beta Catenin; D019826:Cholic Acid