Hippo Signaling Regulates Bile Acid Metabolism And Promotes Tumorigenesis

Bile acids are the main components of bile,which are synthesized in the liver are secreted into the intestinal tract to facilitate the digestion and absorption of nutrients.Most bile acids are reabsorbed by the ileum and are transported back to the liver via the portal blood circulation.FXR-SHP-CYP7A1 is the classic pathway that regulates the metabolism of bile acids,and CYP7A1,the only rate-limiting enzyme,catalyzes the conversion of cholesterol to bile acids in the first step.SHP is an important transcription suppressor to regulate the transcription of Cvp7a1.The other mechanism is that intestinal bile acids act on FXR in ileal enterocytes to induce the expression of mouse fibroblast growth factor 15(FGF15).FGF15 is secreted into the enterohepatic circulation and downregulates Cyp7al expression in the liver to limit bile acid synthesis through hepatic FGFR4 receptor signaling.Recently,bile acids have also been considered as hepatomitogens.Several studies demonstrated that the bile acid concentrations in the liver help control both the start and end of liver regeneration.However,the mechanisms underlying bile acid-mediated liver growth and size control remain largely unknown.The liver generally maintains an appropriate size relative to the rest of the body.Following injury or resection,quiescent liver cells go through a series of well-orchestrated steps to complete regeneration1.How the liver knows when to begin or stop growing is a fundamental unanswered question in liver development,regeneration and cancer biology.The recently discovered Hippo pathway plays a critical role in controlling organ size and homeostasis in many organisms from Drosophila to mammals.When the Hippo pathway is off,the co-activator Yap/Taz translocates to the nucleus and forms a functional hybrid transcriptional factor with TEAD to turn on pro-proliferative and pro-survival genes,thereby enabling cell proliferation.The absence of Hippo signaling pathway in the liver may lead to the disorder of many metabolic processes.We and others have previously demonstrated that the genetic disruption of kinases Mst1/2 or the Yap transgene results in sustained liver growth,leading to a 5-fold increase in liver size within 3 months.Although kinases Mst1/2 could be positively activated by TAO family kinases or blocked by Raf in mammals,the potential identity of extracellular ligands and their cognate receptors that regulate the Hippo pathway remains elusive.In this study,we found that fibroblast growth factor FGF15 activates Hippo signalling cascade to suppress bile acid metabolism,liver overgrowth and tumorigenesis.FGF15 is induced by FXR in ileal enterocytes in response to increased intestinal bile.We found that enterohepatic circulating FGF15 triggers hepatic receptor FGFR4 to activate Hippo kinases Mst1/2.The active Mst1/2 subsequently phosphorylate and stabilize SHP to downregulate the expression of bile acid-synthetic key enzyme CYP7A1,thereby limiting bile acid synthesis.Consistently,loss of FGFR4 led to significantly reduced Mst1/2 activation.Mstl/2 deficiency results in impaired negative feedback suppression of bile acid metabolism,remarkably increased CYP7A1 expression and bile acid production,which further triggers bile acid receptors to enhance Hippo effector Yap activity to promote liver overgrowth.Importantly,pharmacological depletion of intestinal bile acids or genetic inhibition of bile acids synthesizing attenuates Mstl/2-mutant-driven liver overgrowth and oncogenesis.Therefore,FGF15-Hippo signaling along the gut-liver axis acts as a sensor of bile acid availability that controls liver size and cancer development.This study expands the new research field of Hippo signaling pathway,and provides a new idea for the prevention and treatment of liver cancer.