Effective treatment of steatosis and steatohepatitis by fibroblast growth factor 1 in mouse models of nonalcoholic fatty liver disease

Weilin Liu, Dicky Struik, Vera J. M. Nies, Angelika Jurdzinski, Liesbeth Harkema, Alain de Bruin, Henkjan J. Verkade, Michael Downes, Ronald M. Evans, Tim van Zutphen, Johan W. Jonker

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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-gamma (PPAR gamma) 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 PPAR gamma in visceral adipose tissue and as a critical factor in adipose remodeling. Because FGF1 is situated downstream of PPAR gamma, 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.

Original languageEnglish
Pages (from-to)2288-2293
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number8
DOIs
Publication statusPublished - 23-Feb-2016

Keywords

  • FGF1
  • steatosis
  • steatitis
  • NAFLD
  • inflammation
  • FIBROBLAST-GROWTH-FACTOR
  • ACTIVATED RECEPTOR-GAMMA
  • PEROXISOME PROLIFERATOR
  • PPAR-GAMMA
  • EXPRESSION
  • INSULIN
  • GLUCOSE
  • METAANALYSIS
  • SUPPRESSION
  • HOMEOSTASIS

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