Elevated bile acid (BA) concentrations in the liver is associated with severe disease, including cholestasis and hepatocellular carcinoma. The nuclear Farnesoid X Receptor (FXR) is the master regulator of BAs homeostasis. In the ileum, BA-dependent FXR activation induces the production of the fibroblast growth factor FGF19, a hormone that reaches the liver through the portal system where it represses the expression of CYP7A1, the rate limiting enzyme in the process of hepatic BAs synthesis. This gut-liver FXR-FGF19 dual action is the paradigm of physiological BA regulation and it is currently targeted in the clinical practice for liver disease such as primary cholangitis. At a variance of FXR activation, native FGF19 has strong anti-cholestatic and anti-fibrotic activity in the liver but it retains peculiar pro-tumorigenic actions. Thus, novel analogues have been generated to avoid tumorigenic capacity while maintaining BA metabolic action. Here we present a novel and intriguing view on the putative possibility to target the FXR-FGF19 duo in order to offer a bona fide promising therapeutic approach to bile acid promoted hepatocarcinoma.

The gut-liver axis in hepatocarcinoma: a focus on the nuclear receptor FXR and the enterokine FGF19

Piglionica, Marilidia;Cariello, Marica;Moschetta, Antonio
2018-01-01

Abstract

Elevated bile acid (BA) concentrations in the liver is associated with severe disease, including cholestasis and hepatocellular carcinoma. The nuclear Farnesoid X Receptor (FXR) is the master regulator of BAs homeostasis. In the ileum, BA-dependent FXR activation induces the production of the fibroblast growth factor FGF19, a hormone that reaches the liver through the portal system where it represses the expression of CYP7A1, the rate limiting enzyme in the process of hepatic BAs synthesis. This gut-liver FXR-FGF19 dual action is the paradigm of physiological BA regulation and it is currently targeted in the clinical practice for liver disease such as primary cholangitis. At a variance of FXR activation, native FGF19 has strong anti-cholestatic and anti-fibrotic activity in the liver but it retains peculiar pro-tumorigenic actions. Thus, novel analogues have been generated to avoid tumorigenic capacity while maintaining BA metabolic action. Here we present a novel and intriguing view on the putative possibility to target the FXR-FGF19 duo in order to offer a bona fide promising therapeutic approach to bile acid promoted hepatocarcinoma.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11586/221469
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