title: 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.
abstract: 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.
  
  
  
  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) onFGF15/19expression 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 obesedb/dbmice undergoing PH.
  
  
  
  Hepatosteatosis and ER stress were exacerbated in HFD-fedFgf15-/-mice. Hepatic expression ofPparγ2was elevated inFgf15-/-mice, being reversed by FGF19 treatment. PA inducedFGF15/19expression 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 increaseddb/dbmice survival and improved regeneration upon PH.
  
  
  
  FGF15/19 is essential for hepatic metabolic adaptation to dietary fat being a physiological regulator ofPparγ2expression.Perioperative administration of Fibapo improves fatty liver regeneration.
authors.affiliation: Hepatology Programme, CIMA-University of Navarra, IdiSNA, CIBEREHD, Pamplona, Spain.
authors.forename: Gloria
authors.initials: G
authors.lastname: Alvarez-Sola
authors.affiliation: Hepatology Programme, CIMA-University of Navarra, IdiSNA, CIBEREHD, Pamplona, Spain.
authors.forename: Iker
authors.initials: I
authors.lastname: Uriarte
authors.affiliation: Hepatology Programme, CIMA-University of Navarra, IdiSNA, CIBEREHD, Pamplona, Spain.
authors.forename: M Ujue
authors.initials: MU
authors.lastname: Latasa
authors.affiliation: Hepatology Programme, CIMA-University of Navarra, IdiSNA, CIBEREHD, Pamplona, Spain.
authors.forename: Maite G
authors.initials: MG
authors.lastname: Fernandez-Barrena
authors.affiliation: Hepatology Programme, CIMA-University of Navarra, IdiSNA, CIBEREHD, Pamplona, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Urtasun
authors.affiliation: Hepatology Programme, CIMA-University of Navarra, IdiSNA, CIBEREHD, Pamplona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Elizalde
authors.affiliation: Hepatology Programme, CIMA-University of Navarra, IdiSNA, CIBEREHD, Pamplona, Spain.
authors.forename: Marina
authors.initials: M
authors.lastname: Barcena-Varela
authors.affiliation: Hepatology Programme, CIMA-University of Navarra, IdiSNA, CIBEREHD, Pamplona, Spain.
authors.forename: Maddalen
authors.initials: M
authors.lastname: Jiménez
authors.affiliation: Hepatology Programme, CIMA-University of Navarra, IdiSNA, CIBEREHD, Pamplona, Spain.
authors.forename: Haisul C
authors.initials: HC
authors.lastname: Chang
authors.affiliation: Hepatology Programme, CIMA-University of Navarra, IdiSNA, CIBEREHD, Pamplona, Spain.
authors.forename: Roberto
authors.initials: R
authors.lastname: Barbero
authors.affiliation: Metabolic Research Laboratory, Clínica Universidad de Navarra, IdiSNA, CIBEROBN, Pamplona, Spain.
authors.forename: Victoria
authors.initials: V
authors.lastname: Catalán
authors.affiliation: Metabolic Research Laboratory, Clínica Universidad de Navarra, IdiSNA, CIBEROBN, Pamplona, Spain.
authors.forename: Amaia
authors.initials: A
authors.lastname: Rodríguez
authors.affiliation: Metabolic Research Laboratory, Clínica Universidad de Navarra, IdiSNA, CIBEROBN, Pamplona, Spain.
authors.forename: Gema
authors.initials: G
authors.lastname: Frühbeck
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Barcelona, CIBEROBN, Barcelona, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Gallego-Escuredo
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Barcelona, CIBEROBN, Barcelona, Spain.
authors.forename: Aleix
authors.initials: A
authors.lastname: Gavaldà-Navarro
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Barcelona, CIBEROBN, Barcelona, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Villarroya
authors.affiliation: Hepatology Programme, CIMA-University of Navarra, IdiSNA, CIBEREHD, Pamplona, Spain.
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Rodriguez-Ortigosa
authors.affiliation: Hepatology Programme, CIMA-University of Navarra, IdiSNA, CIBEREHD, Pamplona, Spain.
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Corrales
authors.affiliation: Hepatology Programme, CIMA-University of Navarra, IdiSNA, CIBEREHD, Pamplona, Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Prieto
authors.affiliation: Immunology Programme, CIMA-University of Navarra, IdiSNA, Pamplona, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: Berraondo
authors.affiliation: Hepatology Programme, CIMA-University of Navarra, IdiSNA, CIBEREHD, Pamplona, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Berasain
authors.affiliation: Hepatology Programme, CIMA-University of Navarra, IdiSNA, CIBEREHD, Pamplona, Spain.
authors.forename: Matias A
authors.initials: MA
authors.lastname: Avila
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001647:Bile Acids and Salts / Q000378:metabolism; D002460:Cell Line; D059305:Diet, High-Fat; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000235:genetics; D005234:Fatty Liver / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control*; D005346:Fibroblast Growth Factors / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology*; D006207:Half-Life; D006498:Hepatectomy; D006801:Humans; D007082:Ileum / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008115:Liver Regeneration / Q000187:drug effects* / Q000235:genetics; D008297:Male; D051379:Mice; D008820:Mice, Obese; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D019308:Palmitic Acid / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D016632:Apolipoprotein A-I; D001647:Bile Acids and Salts; C117476:FGF19 protein, human; D047495:PPAR gamma; D011993:Recombinant Fusion Proteins; C108526:fibroblast growth factor 15, mouse; D019308:Palmitic Acid; D005346:Fibroblast Growth Factors
keywords: CHOLESTASIS; FATTY LIVER; GROWTH FACTORS; LIVER FAILURE; LIVER REGENERATION