Interestingly transgenic mice that constitutively express

Interestingly, transgenic mice that constitutively express active FXR in the intestine (iVP16FXR) are protected from chemically-induced and genetically-induced cholestasis. This protective effect is attributed to the induction of intestinal FGF15 and repression of hepatic Cyp7a1 expression, downregulation of BA synthesis and upregulation of intestinal BA disposal [32]. De Girolamo et al. demonstrated that intestinal FXR activation protects from hepatocarcinogenesis through a tight control of BA synthesis via the Fgf15/Fgfr4 enterohepatic signaling axis. Moreover, iVP16FXR mice displayed a reduction of liver inflammation, hyperproliferation and collagen deposition and the activation of intestinal FXR protected mice from spontaneous HCC formation even in absence of hepatic FXR []. Taken together, these data strongly indicates that intestinal FXR is a negative modulator of hepatic inflammation and cellular proliferation induced by hepatic toxic bile rna helicase accumulation. In this scenario, semisynthetic and synthetic FXR agonists have been designed to create selective and potent FXR activators that could be beneficial in patients with metabolic disease and HCC. Obeticholic acid (OCA), also known as INT-747, is a selective FXR agonist that was described for the first time in 2002 and is currently used for the treatment of primary biliary cholangitis. The FLINT study demonstrated that long-term OCA administration ameliorates liver fibrosis, steatosis and lobular inflammation, preventing progression and eventually `treating’ non-alcoholic steatohepatitis (NASH) []. Long term studies are definitively required to define the eventual role of INT-747 in the prevention of HCC in patients at risk and/or as a treatment option of HCC. Intriguingly, a dual FXR and membrane bile acid receptor TGR5 agonist named INT-767, a novel semisynthetic 23-sulfate derivative of obeticholic acid, improves the cholestasis phenotype with a reduction of biliary BA output [35]. In db/db mice, INT-767 ameliorates hepatic histological features and decreases the production of pro-inflammatory cytokines [35]. Furthermore, in Abcb4−/− mice FXR activation by long term-administration of INT-767 stimulates Fgf15 at the transcriptional level, thereby repressing hepatic Cyp7a1 expression, triggering a synergistic gut–liver signaling pathway that leads to total serum BAs reduction and HCC prevention []. Thus, INT-767 prevents from spontaneous HCC development via FXR activation by regulating BA synthesis, supporting the eventual therapeutic exploitation of FXR activation in the clinical management of HCC [].
The role of FGF19 in HCC development: friend or foe? The discovery of the role of the enterokine FGF15/19 in the feedback regulation of BA synthesis emphasizes the importance of the crosstalk between the liver and intestine for BA homeostasis [21]. Indeed, FGF15/19 has a key role in the regulation of BA homeostasis through the FXR-mediated Cyp7a1 inhibition [21]. In addition, FGF15/19 is able to reduce glucose synthesis and lowers triglycerides levels, inducing fatty acid oxidation and glycogen and protein synthesis. In mice, the administration of FGF19 protects from diet-induced obesity [37,38]. Elevated FGF19 plasma levels were found in patients with extrahepatic cholestasis, insulin resistance and nonalcoholic fatty liver disease (NAFLD) [39] suggesting that FGF19 modulation might offer a promising therapeutic potential in several metabolic disease. Modica et al. demonstrated, that intestinal FXR overexpression induces FGF15 gene expression and protects liver from cholestasis reducing BA pool size in mice [32]. However, this hormone has been also involved in the development of HCC. Indeed, the expression of FGF19 in transgenic mice induces HCC development between 10 and 12 months of age [40]. In HCC patients, FGF19 expression is up-regulated and is correlated with poor prognosis [41]. The FGF19 tumorigenic activity has been attributed to a cross-talk between FGFR4 and β-catenin [42]. Accordingly, it has been shown that in mice with ectopic FGF19 expression, the use of FGFR4-neutralizing antibody reduced tumor growth, opening to novel therapeutic strategies to limit hepatocyte proliferation [42,43]. Recently, it has been demonstrated that hepatocytes-specific deletion of stat3 and genetic or pharmacological ablation of IL6 are able to inhibit FGF19 induced HCC, with unchanged FGF19 functions on BA, glucose and energy metabolism [].