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Cell Rep. 2013 Nov 27;5(4):1060-9. doi: 10.1016/j.celrep.2013.10.030. Epub 2013 Nov 21.

Bile acids activate YAP to promote liver carcinogenesis.

Author information

  • 1Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, IL 61801, USA. Electronic address: anakk@illinois.edu.
  • 2Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, IL 61801, USA.
  • 3Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
  • 4Department of Biochemistry and Molecular Biology, MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 5Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA.
  • 6Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: moore@bcm.edu.

Abstract

Elevated bile acid levels increase hepatocellular carcinoma by unknown mechanisms. Here, we show that mice with a severe defect in bile acid homeostasis due to the loss of the nuclear receptors FXR and SHP have enlarged livers, progenitor cell proliferation, and Yes-associated protein (YAP) activation and develop spontaneous liver tumorigenesis. This phenotype mirrors mice with loss of hippo kinases or overexpression of their downstream target, YAP. Bile acids act as upstream regulators of YAP via a pathway dependent on the induction of the scaffold protein IQGAP1. Patients with diverse biliary dysfunctions exhibit enhanced IQGAP1 and nuclear YAP expression. Our findings reveal an unexpected mechanism for bile acid regulation of liver growth and tumorigenesis via the Hippo pathway.

Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

PMID:
24268772
[PubMed - indexed for MEDLINE]
PMCID:
PMC3961013
Free PMC Article

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