Bile acids synthesized in the liver are

Bile acids synthesized in the liver are secreted into the intestinal tract to facilitate the digestion and FPH1 mg of nutrients. Most bile acids are reabsorbed by the ileum and are transported back to the liver via the portal blood circulation. Recently, bile acids have also been considered as hepatomitogens (Anakk et al., 2013, Huang et al., 2006, Huang et al., 2009, Otao et al., 2012, Ueda et al., 2002). Bile acid levels are tightly controlled by a feedback regulatory pathway in which activating the nuclear receptor FXR represses transcription of the Cyp7a1 gene, which encodes the rate-limiting enzyme in the classic bile acid synthesis pathway (Choi et al., 2006, Fon Tacer et al., 2010, Goodwin et al., 2000, Inagaki et al., 2005, Kerr et al., 2002, Lu et al., 2000, Parks et al., 1999, Wang et al., 2002). Two distinct mechanisms of Cyp7a1 repression by hepatic and intestinal FXR have been proposed. One involves the ability of the orphan nuclear receptor SHP in the liver, where its expression is regulated by FXR, to interact with the transcription factors LRH-1 and HNF4α to repress Cyp7a1 expression. 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 exclusively induced by intestinal but not hepatic FXR and secreted into the enterohepatic circulation and downregulates Cyp7a1 expression in the liver to limit bile acid synthesis through hepatic FGFR4 receptor signaling (Kliewer and Mangelsdorf, 2015, Ornitz and Itoh, 2015). Interestingly, due to the lack of mouse FGF15 activity toward the human hepatic receptor FGFR4, the sizes of livers repopulated with human hepatocytes in immune-deficient Fah−/−, Rag2−/−, Il2r−/−, NOD (FRGN) mice were almost three times bigger than those in FRGN19+ animals in which the human FGFR4 ligand FGF19 transgene, a human ortholog of mouse FGF15, was introduced (Naugler et al., 2015). These findings indicate that FGF15/19 could be a critical factor for liver size control. However, the mechanisms underlying bile acid-mediated liver growth and size control remain largely unknown.
Results
Discussion A previous study demonstrated that lacking human FGFR4 ligand, FGF19, larger livers were found in FRGN mice repopulated with human hepatocytes (Naugler et al., 2015). Loss of FGFR4 in mouse liver results in liver cancer formation (Luo et al., 2010). Similarly, we found that an AAV expressing FGF15 significantly reduced liver growth and size, indicating that FGF15/19 is a critical factor for liver growth and size control. In contrast, FGFR4 was shown to be upregulated in human liver cancers where FGFR4 could induce several oncogenic signaling pathways including Ras-Raf-MapK and PI3K-Akt (Sandhu et al., 2014, Sawey et al., 2011, Turner and Grose, 2010). These findings indicate that FGFR4 could promote pro-oncogenic and anti-oncogenic signaling. We demonstrate that NF2 functions as a molecular switch to turn on FGF15/FGFR4-induced Mst1/2 activation and attenuate ERK signaling. We further identified FGFR4-mediated phosphoryation of tyrosine residue 207 of NF2 as a key tumor suppression mechanism. NF2 is implicated in the development of multiple cancers in humans and mice (Benhamouche et al., 2010, Curto et al., 2007, Giovannini et al., 2000, Hamaratoglu et al., 2006, McClatchey et al., 1998). Importantly, we found that NF2 expression was commonly downregulated in human HCC, implying that NF2-mediated Mst1/2 activation is a key tumor suppressor mechanism of FGF15/FGFR4 signaling; upregulated FGFR4 expression might be a negative feedback signal due to the loss of NF2 in human HCC. Thus, enterohepatic FGF15-FGFR4-Mst1/2 signaling is critical for liver size control and cancer suppression. It will be interesting to determine the underlying mechanism by which NF2 gene expression and its protein stability are regulated in normal liver tissue and HCC and whether an AAV expressing NF2 could block liver cancer formation.