Fibroblast growth factor 1 (FGF1) is critical for adipose tissue remodeling under conditions of dietary stress. Pharmacological treatment with recombinant FGF1 (rFGF1) has potent glucose-lowering, insulin-sensitizing, and antisteatotic effects in hyperglycemic mouse models, but the mechanism is largely unknown. Here we characterize the effects of rFGF1 on nonalcoholic liver disease in two etiologically different mouse models. Strong antisteatotic effects of rFGF1 were observed in ob/ob mice but not in choline-deficient mice, suggesting that rFGF1 exerts its antisteatotic effect via processes specifically impaired in choline-deficient mice, such as lipid oxidation and lipoprotein secretion. In contrast, hepatic inflammation and alanine aminotransferase levels were reduced in both models, indicating that these effects are independent of the antisteatotic properties of rFGF1.

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.