Objective Fibroblast growth factor 15/19 (FGF15/19), an enterokine that regulates synthesis of hepatic bile acids (BA), has been proposed to influence fat metabolism. Without FGF15/19, mouse liver regeneration after partial hepatectomy (PH) is severely impaired. We studied the role of FGF15/19 in response to a high fat diet (HFD) and its regulation by saturated fatty acids. We developed a fusion molecule encompassing FGF19 and apolipoprotein A-I, termed Fibapo, and evaluated its pharmacological properties in fatty liver regeneration.
Design Fgf15−/− mice were fed a HFD. Liver fat and the expression of fat metabolism and endoplasmic reticulum (ER) stress-related genes were measured. Influence of palmitic acid (PA) on FGF15/19 expression was determined in mice and in human liver cell lines. In vivo half-life and biological activity of Fibapo and FGF19 were compared. Hepatoprotective and proregenerative activities of Fibapo were evaluated in obese db/db mice undergoing PH.
Results Hepatosteatosis and ER stress were exacerbated in HFD-fed Fgf15−/− mice. Hepatic expression of Pparγ2 was elevated in Fgf15−/− mice, being reversed by FGF19 treatment. PA induced FGF15/19 expression in mouse ileum and human liver cells, and FGF19 protected from PA-mediated ER stress and cytotoxicity. Fibapo reduced liver BA and lipid accumulation, inhibited ER stress and showed enhanced half-life. Fibapo provided increased db/db mice survival and improved regeneration upon PH.
Conclusions FGF15/19 is essential for hepatic metabolic adaptation to dietary fat being a physiological regulator of Pparγ2 expression. Perioperative administration of Fibapo improves fatty liver regeneration.
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MAA and CB share senior authorship. GA-S and IU made equal contribution to the study.
Contributors GA-S, IU, MUL, RU, ME, MB-V, MJ, HCC and CR-O performed in vitro and in vivo experiments and collected data. VC, AR, JMG-E and AG-N analysed human samples and collected data. GA-S, IU, FJC, JP, PB, FV, GF, CB and MAA designed experiments and discussed the data. IU, CB and MAA wrote and submitted the manuscript.
Funding This work was funded by CIBERehd; Grants FIS PI13/00359, PI13/00385 and PI16/01126 from Instituto de Salud Carlos III (ISCIII), co-financed by ‘Fondo Europeo de Desarrollo Regional’ (FEDER) ‘Una manera de hacer Europa’. ‘Adipoplast’ Network (BFU2015-70454-REDT). ‘Ramón y Cajal-I3’ contract to MUL. Marie Curie EU contract to MGF-B. ADA-University of Navarra fellowship to MJ; FPI fellowship from Ministerio de Economía to MB-V; Fundación Eugenio Rodríguez Pascual; Fundación M Torres; Fundación Mario Losantos; Fundación Familia Puig-Infante. We also thank Mr. Eduardo Avila Zaragozá for his generous support.
Competing interests Not declared.
Ethics approval The University Clinic of Navarra and the Santa Creu i Sant Pau Hospital Ethics.
Provenance and peer review Not commissioned; externally peer reviewed.
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