RM Gadaleta1,2, N Scialpi1, C Peres2, M Cariello1, B Ko3, J Luo3, A Moschetta11Interdisciplinary Dept of Medicine, University of Bari, Italy2National Institute of Biostructure and Biosystem, INBB, Rome, Italy3NGM... [ view full abstract ]
RM Gadaleta1,2, N Scialpi1, C Peres2, M Cariello1, B Ko3, J Luo3, A Moschetta1
1Interdisciplinary Dept of Medicine, University of Bari, Italy
2National Institute of Biostructure and Biosystem, INBB, Rome, Italy
3NGM Biopharmaceuticals, South S Francisco, CA, USA
Critical regulation of bile acid (BA) concentration within the enterohepatic circulation occurs via an intensive molecular crosstalk between the liver and gut, orchestrated by tissue-specific FXR activities. Disruption of BA homeostasis has been linked to an increased incidence of gut/liver axis-related disease including hepatocellular carcinoma (HCC). BAs have inherent detergent properties and, if their levels are elevated act as tumor promoters by inducing inflammation, hyperproliferation and resistance to apoptosis. Maintenance of BA homeostasis requires a fine control of BA synthesis with the enteric farnesoid X receptor (FXR)/fibroblast growth factor 19 (FGF19) axis being a cardinal gatekeeper. We have previously shown that specific intestinal FXR activation is sufficient to restore BA homeostasis in Fxr-KO mice, thus protecting them from age-related hepatic inflammation, fibrosis, and HCC. We here show for the first time the therapeutic exploitation of intestinal FXR/FGF19 axis activation in HCC. Using MDR2-KO and FXR-KO mouse models of spontaneous HCC, we explored the role of FGF19 signaling pathway in age-related fibrosis and carcinogenesis. Male 8-weeks-old mice received a single intravenous dose of adeno-associated virus (AAV) containing genes encoding either control green fluorescent protein (GFP) or a novel engineered variant of FGF19 protein which fully retains BA regulatory activity but is devoid of murine pro-tumoral activity (AAV-FGF19-analogue). FGF19-analogue-treated MDR2-KO and FXR-KO mice are protected from HCC in terms of tumor number/size, liver damage biochemical parameters proliferative and inflammatory genes expression compared to GFP-treated mice. Moreover, expression of the BA synthesis rate-limiting enzyme Cyp7a1 is inhibited in FGF19-analogue-treated compared to GFP-treated mice. Our data strongly suggest the great therapeutic potential of targeting FXR-FGF19 axis in the control of BA-associated risk of HCC development.
