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

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. [Display omitted] •FGF15 activates Mst1/2 through hepatic FGFR4 in response to increased bile acids•NF2 switches FGFR4’s role from pro-oncogenic to anti-tumor signaling via Mst1/2•Mst1/2 acts as a key negative feedback suppressor of bile acid synthesis via SHP•Depletion of bile acids retards Mst1/2-mutant-driven liver growth and oncogenesis The external factors that modulate Hippo signaling remain elusive. Ji et al. demonstrate that FGF15-Hippo signaling along the gut-liver axis acts as a sensor of bile acid availability for liver size control and tumor suppression.