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

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.

Author information

1
Hepatology Programme, CIMA-University of Navarra, IdiSNA, CIBEREHD, Pamplona, Spain.
2
Metabolic Research Laboratory, Clínica Universidad de Navarra, IdiSNA, CIBEROBN, Pamplona, Spain.
3
Department of Biochemistry and Molecular Biology, University of Barcelona, CIBEROBN, Barcelona, Spain.
4
Immunology Programme, CIMA-University of Navarra, IdiSNA, Pamplona, Spain.

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.

KEYWORDS:

CHOLESTASIS; FATTY LIVER; GROWTH FACTORS; LIVER FAILURE; LIVER REGENERATION

PMID:
28119353
DOI:
10.1136/gutjnl-2016-312975
[Indexed for MEDLINE]

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