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Sci Rep. 2014 Oct 30;4:6835. doi: 10.1038/srep06835.

Loss of α-catenin elicits a cholestatic response and impairs liver regeneration.

Author information

1
Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Singapore, Singapore.
2
Mechanobiology Institute, National University of Singapore, Singapore.
3
Koch Institute for Integrative Cancer Research, MIT, Massachusetts, U.S.A.
4
1] Koch Institute for Integrative Cancer Research, MIT, Massachusetts, U.S.A [2] Department of Biology, MIT, Massachusetts, U.S.A [3] Institute for Medical Engineering and Science, MIT, Massachusetts, U.S.A.
5
Department of Anatomy, National University of Singapore, Singapore.
6
Translational Laboratory in Genetic Medicine, A*STAR, Singapore, Singapore.
7
1] Koch Institute for Integrative Cancer Research, MIT, Massachusetts, U.S.A [2] Institute for Medical Engineering and Science, MIT, Massachusetts, U.S.A [3] Department of Chemical Engineering, MIT, Massachusetts, U.S.A [4] Department of Anaesthesiology, Children's Hospital Boston, Harvard Medical School, Massachusetts, U.S.A.
8
Skolkovo Institute of Science and Technology ul, Skolkovo, Russian Federation.
9
1] Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Singapore, Singapore [2] Department of Biochemistry School of Medicine National University of Singapore, Singapore [3] Cancer Science Institute National University of Singapore, Singapore.

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.

PMID:
25355493
PMCID:
PMC4213774
DOI:
10.1038/srep06835
[Indexed for MEDLINE]
Free PMC Article

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