Article Text

PDF
Original article
Fibroblast growth factor 15/19 (FGF15/19) protects from diet-induced hepatic steatosis: development of an FGF19-based chimeric molecule to promote fatty liver regeneration
  1. Gloria Alvarez-Sola1,
  2. Iker Uriarte1,
  3. M Ujue Latasa1,
  4. Maite G Fernandez-Barrena1,
  5. Raquel Urtasun1,
  6. Maria Elizalde1,
  7. Marina Barcena-Varela1,
  8. Maddalen Jiménez1,
  9. Haisul C Chang1,
  10. Roberto Barbero1,
  11. Victoria Catalán2,
  12. Amaia Rodríguez2,
  13. Gema Frühbeck2,
  14. José M Gallego-Escuredo3,
  15. Aleix Gavaldà-Navarro3,
  16. Francesc Villarroya3,
  17. Carlos M Rodriguez-Ortigosa1,
  18. Fernando J Corrales1,
  19. Jesus Prieto1,
  20. Pedro Berraondo4,
  21. Carmen Berasain1,
  22. Matias A Avila1
  1. 1Hepatology Programme, CIMA-University of Navarra, IdiSNA, CIBEREHD, Pamplona, Spain
  2. 2Metabolic Research Laboratory, Clínica Universidad de Navarra, IdiSNA, CIBEROBN, Pamplona, Spain
  3. 3Department of Biochemistry and Molecular Biology, University of Barcelona, CIBEROBN, Barcelona, Spain
  4. 4Immunology Programme, CIMA-University of Navarra, IdiSNA, Pamplona, Spain
  1. Correspondence to Professor Matias A Avila and Carmen Berasain. CIMA-University of Navarra, Avda. Pio XII, n55. Pamplona 31008, Spain; maavila{at}unav.es; cberasain{at}unav.es

Abstract

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.

Statistics from Altmetric.com

Footnotes

  • 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.

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Linked Articles