Bile acids activate YAP to promote liver carcinogenesis.

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.

• Authors: Sayeepriyadarshini Anakk, Manoj Bhosale, Valentina A Schmidt, Randy L Johnson, Milton J Finegold, David D Moore
• Journal: Cell reports (Cell Rep) Vol. 5 Issue 4 Pg. 1060-9 (Nov 27 2013) ISSN: 2211-1247 [Electronic] United States
• PMID: 24268772 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Adaptor Proteins, Signal Transducing
• Bile Acids and Salts
• Cell Cycle Proteins
• IQ motif containing GTPase activating protein 1
• Phosphoproteins
• Proto-Oncogene Proteins
• Receptors, Cytoplasmic and Nuclear
• Transcription Factors
• YAP-Signaling Proteins
• YAP1 protein, human
• Yap1 protein, mouse
• macrophage stimulating protein
• nuclear receptor subfamily 0, group B, member 2
• ras GTPase-Activating Proteins
• farnesoid X-activated receptor
• Hepatocyte Growth Factor
• Protein Serine-Threonine Kinases
• Serine-Threonine Kinase 3
• Stk3 protein, mouse

Topics

• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• Adolescent
• Animals
• Bile Acids and Salts (metabolism)
• Carcinogenesis
• Carcinoma, Hepatocellular (genetics, pathology)
• Cell Cycle Proteins
• Cells, Cultured
• Child
• Child, Preschool
• Enzyme Activation (genetics)
• Hepatocyte Growth Factor (genetics)
• Hippo Signaling Pathway
• Humans
• Infant
• Infant, Newborn
• Liver Neoplasms (genetics, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Phosphoproteins (genetics, metabolism)
• Protein Serine-Threonine Kinases (genetics)
• Proto-Oncogene Proteins (genetics)
• Receptors, Cytoplasmic and Nuclear (genetics)
• Serine-Threonine Kinase 3
• Transcription Factors
• YAP-Signaling Proteins
• ras GTPase-Activating Proteins (biosynthesis, genetics, metabolism)