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 cholinedeficient 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 insulinsensitizing effects, rFGF1 could be therapeutically effective in the treatment of NAFLD.

Resistance to visceral obesity is associated with increased locomotion in mice expressing an endothelial cell‐specific fibroblast growth factor 1 transgene

“…Both FGF1 (Liu et al. ) and adiponectin (Polyzos et al. ) have been shown to protect against nonalcoholic fatty liver disease (NAFLD), but whether or not FGF1 is acting through adiponectin or both work synergistically via different mechanisms to prevent this life‐threatening condition is not reported.…”

An S116R Phosphorylation Site Mutation in Human Fibroblast Growth Factor-1 Differentially Affects Mitogenic and Glucose-Lowering Activities

“…45 The glucose-lowering effect of FGF-1 in ob/ob mice is dependent on FGFR-1c activation in adipose tissue. 86 Furthermore, antibody-mediated activation of FGFR-1 ameliorates type II diabetes 87 ; thus, intracrine activity of FGF-1 is independent of the glucose-lowering functionality. Systemic delivery of FGF-1 results in rapid sequestration on HS.…”

Partnering with Science: New Hope for the Effective Treatment of Type 2 Diabetes

“…During 2012-2016, Dr. Ronald Evans at the Salk Institute published a series of papers showing that another member of the FGF family, FGF-1, had a very potent activity related to fat remodeling and glucose regulation [3][4][5]. This was another unexpected result, since previous studies of FGF-1 knockout mice (genetically modified mice with inactive FGF-1 genes) identified no physiological effect.…”