2. Academic Validation
  3. FGF15 Activates Hippo Signaling to Suppress Bile Acid Metabolism and Liver Tumorigenesis

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

  • Dev Cell. 2019 Feb 25;48(4):460-474.e9. doi: 10.1016/j.devcel.2018.12.021.
Suyuan Ji 1,  Qingxu Liu 1,  Shihao Zhang 1,  Qinghua Chen 2,  Cong Wang 3,  Weiji Zhang 2,  Chen Xiao 2,  Yuxi Li 2,  Cheng Nian 2,  Jiaxin Li 2,  Junhong Li 2,  Jing Geng 2,  Lixin Hong 2,  Changchuan Xie 2,  Ying He 2,  Xing Chen 4,  Xun Li 4,  Zhen-Yu Yin 5,  Han You 2,  Kwang-Huei Lin 6,  Qiao Wu 2,  Chundong Yu 2,  Randy L Johnson 7,  Li Wang 8,  Lanfen Chen 2,  Fen Wang 9,  Dawang Zhou 10
Affiliations

Affiliations

  • 1 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; Cancer Research Center of Xiamen University, Xiamen, Fujian 361102, China.
  • 2 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
  • 3 School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang 325030, China.
  • 4 Department of Laboratory Medicine, The First Affiliated Hospital, Medical College of Xiamen University, Xiamen, Fujian 361003, China.
  • 5 Department of Hepatobiliary Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian 361004, China.
  • 6 Department of Biochemistry, College of Medicine, Chang Gung University, Liver Research Center, Chang Gung Memorial Hospital, TaoYuan 333, Taiwan.
  • 7 Department of Biochemistry and Molecular Biology, University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
  • 8 Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT 06269, USA; The Institute for Systems Genomics, University of Connecticut, Storrs, CT 06269, USA.
  • 9 Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA.
  • 10 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; Cancer Research Center of Xiamen University, Xiamen, Fujian 361102, China. Electronic address: dwzhou@xmu.edu.cn.
PMID: 30745141 DOI: 10.1016/j.devcel.2018.12.021
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.

Keywords

FGF15; FGFR4; HCC; Hippo signaling; NF2; SHP; bile acid metabolism; liver growth.

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