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

Gut. 2017 Oct;66(10):1818-1828. doi: 10.1136/gutjnl-2016-312975. Epub 2017 Jan 24.


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.


Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apolipoprotein A-I / genetics
  • Apolipoprotein A-I / metabolism
  • Apoptosis / drug effects
  • Bile Acids and Salts / metabolism
  • Cell Line
  • Diet, High-Fat
  • Endoplasmic Reticulum Stress / drug effects*
  • Endoplasmic Reticulum Stress / genetics
  • Fatty Liver / genetics*
  • Fatty Liver / metabolism
  • Fatty Liver / prevention & control*
  • Fibroblast Growth Factors / genetics*
  • Fibroblast Growth Factors / metabolism
  • Fibroblast Growth Factors / pharmacology*
  • Half-Life
  • Hepatectomy
  • Humans
  • Ileum / metabolism
  • Lipid Metabolism / genetics
  • Liver / metabolism
  • Liver Regeneration / drug effects*
  • Liver Regeneration / genetics
  • Male
  • Mice
  • Mice, Obese
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Palmitic Acid / pharmacology
  • Protein Biosynthesis / drug effects
  • Recombinant Fusion Proteins / metabolism
  • Recombinant Fusion Proteins / pharmacokinetics
  • Recombinant Fusion Proteins / pharmacology*
  • Up-Regulation


  • Apolipoprotein A-I
  • Bile Acids and Salts
  • FGF19 protein, human
  • PPAR gamma
  • Recombinant Fusion Proteins
  • fibroblast growth factor 15, mouse
  • Palmitic Acid
  • Fibroblast Growth Factors