FGF15 Activates Hippo Signaling to Suppress Bile Acid Metabolism and Liver Tumorigenesis.

Abstract

The external factors that modulate Hippo signaling remain elusive. Here, we report that FGF15 activates Hippo signaling to suppress bile acid metabolism, liver overgrowth, and tumorigenesis. FGF15 is induced by FXR in ileal enterocytes in response to increased amounts of intestinal bile. We found that circulating enterohepatic FGF15 stimulates hepatic receptor FGFR4 to recruit and phosphorylate NF2, which relieves the inhibitory effect of Raf on the Hippo kinases Mst1/2, thereby switching FGFR4's role from pro-oncogenic to anti-tumor signaling. The activated Mst1/2 subsequently phosphorylates and stabilizes SHP to downregulate the key bile acid-synthesis enzyme Cyp7a1 expression, thereby limiting bile acid synthesis. In contrast, Mst1/2 deficiency impairs bile acid metabolism and remarkably increases Cyp7a1 expression and bile acid production. Importantly, pharmacological depletion of intestinal bile abrogates Mst1/2-mutant-driven liver overgrowth and oncogenesis. Therefore, FGF15-Hippo signaling along the gut-liver axis acts as a sensor of bile acid availability to restrain liver size and tumorigenesis.

• Authors: Suyuan Ji, Qingxu Liu, Shihao Zhang, Qinghua Chen, Cong Wang, Weiji Zhang, Chen Xiao, Yuxi Li, Cheng Nian, Jiaxin Li, Junhong Li, Jing Geng, Lixin Hong, Changchuan Xie, Ying He, Xing Chen, Xun Li, Zhen-Yu Yin, Han You, Kwang-Huei Lin, Qiao Wu, Chundong Yu, Randy L Johnson, Li Wang, Lanfen Chen, Fen Wang, Dawang Zhou
• Journal: Developmental cell (Dev Cell) Vol. 48 Issue 4 Pg. 460-474.e9 (02 25 2019) ISSN: 1878-1551 [Electronic] United States
• PMID: 30745141 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018. Published by Elsevier Inc.

Chemical References

• Bile Acids and Salts
• fibroblast growth factor 15, mouse
• Fibroblast Growth Factors
• FGFR4 protein, human
• Receptor, Fibroblast Growth Factor, Type 4
• Protein Serine-Threonine Kinases

Topics

• Animals
• Bile Acids and Salts (metabolism)
• Carcinogenesis (metabolism)
• Fibroblast Growth Factors (metabolism)
• Hippo Signaling Pathway
• Humans
• Lipid Metabolism (genetics, physiology)
• Liver Neoplasms (metabolism)
• Mice, Transgenic
• Protein Serine-Threonine Kinases (metabolism)
• Receptor, Fibroblast Growth Factor, Type 4 (metabolism)
• Signal Transduction (physiology)