1. Loss of α-catenin elicits a cholestatic response and impairs liver regeneration.
- Author
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Herr KJ, Tsang YH, Ong JW, Li Q, Yap LL, Yu W, Yin H, Bogorad RL, Dahlman JE, Chan YG, Bay BH, Singaraja R, Anderson DG, Koteliansky V, Viasnoff V, and Thiery JP
- Subjects
- Actins metabolism, Adaptor Proteins, Signal Transducing metabolism, Animals, Bile Canaliculi pathology, Bile Canaliculi ultrastructure, Cell Cycle Proteins, Cell Proliferation, Cholestasis blood, Female, Hepatocytes physiology, Mice, Mice, Knockout, Microvilli ultrastructure, Models, Animal, Phosphoproteins metabolism, YAP-Signaling Proteins, alpha Catenin deficiency, Cholestasis genetics, Liver Regeneration physiology, alpha Catenin genetics
- Abstract
The liver is unique in its capacity to regenerate after injury, during which hepatocytes actively divide and establish cell-cell contacts through cell adhesion complexes. Here, we demonstrate that the loss of α-catenin, a well-established adhesion component, dramatically disrupts liver regeneration. Using a partial hepatectomy model, we show that regenerated livers from α-catenin knockdown mice are grossly larger than control regenerated livers, with an increase in cell size and proliferation. This increased proliferation correlated with increased YAP activation, implicating α-catenin in the Hippo/YAP pathway. Additionally, α-catenin knockdown mice exhibited a phenotype reminiscent of clinical cholestasis, with drastically altered bile canaliculi, elevated levels of bile components and signs of jaundice and inflammation. The disrupted regenerative capacity is a result of actin cytoskeletal disorganisation, leading to a loss of apical microvilli, dilated lumens in the bile canaliculi, and leaky tight junctions. This study illuminates a novel, essential role for α-catenin in liver regeneration.
- Published
- 2014
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