title: Effective treatment of steatosis and steatohepatitis by fibroblast growth factor 1 in mouse models of nonalcoholic fatty liver disease.
abstract: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder and is strongly associated with obesity and type 2 diabetes. Currently, there is no approved pharmacological treatment for this disease, but improvement of insulin resistance using peroxisome proliferator-activated receptor-γ (PPARγ) agonists, such as thiazolidinediones (TZDs), has been shown to reduce steatosis and steatohepatitis effectively and to improve liver function in patients with obesity-related NAFLD. However, this approach is limited by adverse effects of TZDs. Recently, we have identified fibroblast growth factor 1 (FGF1) as a target of nuclear receptor PPARγ in visceral adipose tissue and as a critical factor in adipose remodeling. Because FGF1 is situated downstream of PPARγ, it is likely that therapeutic targeting of the FGF1 pathway will eliminate some of the serious adverse effects associated with TZDs. Here we show that pharmacological administration of recombinant FGF1 (rFGF1) effectively improves hepatic inflammation and damage in leptin-deficient ob/ob mice and in choline-deficient mice, two etiologically different models of NAFLD. Hepatic steatosis was effectively reduced only in ob/ob mice, suggesting that rFGF1 stimulates hepatic lipid catabolism. Potentially adverse effects such as fibrosis or proliferation were not observed in these models. Because the anti-inflammatory effects were observed in both the presence and absence of the antisteatotic effects, our findings further suggest that the anti-inflammatory property of rFGF1 is independent of its effect on lipid catabolism. Our current findings indicate that, in addition to its potent glucose-lowering and insulin-sensitizing effects, rFGF1 could be therapeutically effective in the treatment of NAFLD.
authors: Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands;
authors: Weilin
authors: W
authors: Liu
authors: Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands;
authors: Dicky
authors: D
authors: Struik
authors: Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands;
authors: Vera J M
authors: VJ
authors: Nies
authors: Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands;
authors: Angelika
authors: A
authors: Jurdzinski
authors: Dutch Molecular Pathology Center, Faculty of Veterinary Medicine, Utrecht University, 3584 CL Utrecht, The Netherlands;
authors: Liesbeth
authors: L
authors: Harkema
authors: Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; Dutch Molecular Pathology Center, Faculty of Veterinary Medicine, Utrecht University, 3584 CL Utrecht, The Netherlands;
authors: Alain
authors: A
authors: de Bruin
authors: Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands;
authors: Henkjan J
authors: HJ
authors: Verkade
authors: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037.
authors: Michael
authors: M
authors: Downes
authors: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037 j.w.jonker@umcg.nl evans@salk.edu.
authors: Ronald M
authors: RM
authors: Evans
authors: Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands;
authors: Tim
authors: T
authors: van Zutphen
authors: Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; j.w.jonker@umcg.nl evans@salk.edu.
authors: Johan W
authors: JW
authors: Jonker
mesh_terms: D000818:Animals; D002796:Choline Deficiency / Q000150:complications; D004195:Disease Models, Animal; D016220:Fibroblast Growth Factor 1 / Q000627:therapeutic use*; D015870:Gene Expression; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D020738:Leptin / Q000172:deficiency; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000067996:RAW 264.7 Cells; D011994:Recombinant Proteins / Q000627:therapeutic use; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics
chemical_list: D020738:Leptin; D011994:Recombinant Proteins; D019010:Vascular Cell Adhesion Molecule-1; D016220:Fibroblast Growth Factor 1
keywords: FGF1; NAFLD; inflammation; steatitis; steatosis