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
| Autor: | Carmen Berasain, Marina Bárcena-Varela, C.M. Rodriguez-Ortigosa, Jesús Prieto, Maite G. Fernandez-Barrena, Aleix Gavaldà-Navarro, Maddalen Jimenez, Roberto Barbero, M.R. Elizalde, Gema Frühbeck, Victoria Catalán, Raquel Urtasun, Amaia Rodríguez, Haisul C.Y. Chang, M. Ujue Latasa, Iker Uriarte, Fernando J. Corrales, Matías A. Avila, Gloria Alvarez-Sola, Pedro Berraondo, José M. Gallego-Escuredo, Francesc Villarroya |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty Apolipoprotein B Recombinant Fusion Proteins Palmitic Acid Mice Obese Apoptosis Diet High-Fat Article Cell Line Bile Acids and Salts 03 medical and health sciences Mice Ileum Internal medicine medicine Animals Hepatectomy Humans biology Apolipoprotein A-I FGF15 Fatty liver Gastroenterology Lipid metabolism FGF19 medicine.disease Endoplasmic Reticulum Stress Lipid Metabolism Liver regeneration 3. Good health Liver Regeneration Up-Regulation Fatty Liver Fibroblast Growth Factors PPAR gamma 030104 developmental biology Endocrinology Liver FGF15/19 Protein Biosynthesis biology.protein Steatosis Half-Life |
| Zdroj: | Gut |
| ISSN: | 0017-5749 |
| DOI: | 10.1136/gutjnl-2016-312975 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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