2018
DOI: 10.1038/s41598-018-35496-z
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Suppression of Hepatic Bile Acid Synthesis by a non-tumorigenic FGF19 analogue Protects Mice from Fibrosis and Hepatocarcinogenesis

Abstract: Critical regulation of bile acid (BA) pool size and composition occurs via an intensive molecular crosstalk between the liver and gut, orchestrated by the combined actions of the nuclear Farnesoid X receptor (FXR) and the enterokine fibroblast growth factor 19 (FGF19) with the final aim of reducing hepatic BA synthesis in a negative feedback fashion. Disruption of BA homeostasis with increased hepatic BA toxic levels leads to higher incidence of hepatocellular carcinoma (HCC). While native FGF19 has anti-chole… Show more

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Cited by 46 publications
(37 citation statements)
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“…We conclude that hepatic bile acid synthesis via the classical pathway to produce CA is more affected by UDCA treatment than intra-and extra-hepatic synthesis of CDCA via the alternative pathway, secondary to the hepatic action of FGF19. This is consistent with the effect of FGF19 analogue administration, where the bile acid profile in mice reduces CA in favour of MCA synthesis 22 . In the murine model, treatment with UDCA alone or in combination with CA did not reduce βMCA.…”
Section: Discussionsupporting
confidence: 88%
“…We conclude that hepatic bile acid synthesis via the classical pathway to produce CA is more affected by UDCA treatment than intra-and extra-hepatic synthesis of CDCA via the alternative pathway, secondary to the hepatic action of FGF19. This is consistent with the effect of FGF19 analogue administration, where the bile acid profile in mice reduces CA in favour of MCA synthesis 22 . In the murine model, treatment with UDCA alone or in combination with CA did not reduce βMCA.…”
Section: Discussionsupporting
confidence: 88%
“…Many of FGF19 targets are related to metabolism and proliferation [23]. Several experiments have demonstrated that FGF19 exerts a protective effect against liver fibrosis [24][25][26][27]. Binding to FGFR4 is required for FGF19 proliferative function in mouse livers [28,29].…”
Section: Discussionmentioning
confidence: 99%
“…According to preclinical data, FGF19-M52 maintains the beneficial metabolic effects while lacking mitogenic activity and significantly decreases tumor incidence and size in genetic models of HCC. 440 Moreover, NGM282 (phase 2, NGM Biopharmaceuticals) decreased the NAFLD activity score (NAS) by R2 points in more than 50% of patients in a 12-week clinical trial, thus encouraging further studies in this direction. 441 Several other potential drug targets aimed at promoting histological NASH resolution and/or improving liver fibrosis in patients with advanced or high-risk NAFLD are currently being explored in clinical trials.…”
Section: Llmentioning
confidence: 99%