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. <i>Fgf15^-/-</i> 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 <i>FGF15/19</i> 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 <i>db/db</i> mice undergoing PH. Hepatosteatosis and ER stress were exacerbated in HFD-fed <i>Fgf15^-/-</i> mice. Hepatic expression of <i>Pparγ2</i> was elevated in <i>Fgf15^-/-</i> mice, being reversed by FGF19 treatment. PA induced <i>FGF15/19</i> 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 <i>db/db</i> mice survival and improved regeneration upon PH. FGF15/19 is essential for hepatic metabolic adaptation to dietary fat being a physiological regulator of <i>Pparγ2</i> expression<i>.</i> Perioperative administration of Fibapo improves fatty liver regeneration.