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

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.Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in developed countries and is strongly associated with obesity and type 2 diabetes (1). NAFLD refers to a wide spectrum of liver disorders ranging from simple fatty liver (steatosis) to nonalcoholic steatohepatitis (NASH) with increased risk of developing progressive fibrosis, cirrhosis, and liver cancer (2).Treatment options for NAFLD are limited and are directed mainly at weight loss or pharmacological improvement of insulin resistance (3). Although no pharmacologic therapy has been approved, the thiazolidinedione (TZD) class of insulin sensitizers has been demonstrated to improve steatosis, steatohepatitis, and liver function in mice and patients with NAFLD (1). TZDs improve insulin sensitivity through activation of nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARγ), which reduces insulin resistance in adipose tissue, liver, and skeletal muscle (4). The exact mechanism by which PPARγ exerts its beneficial effects on NAFLD is not completely understood, but it is believed that improved hepatic insulin sensitivity enhances lipid oxidation and reduces hepatic lipogenesis, thereby reducing steatosis (5). In addition, increased peripheral insulin sensitivity may reduce lipolysis in white adipose tissue and thereby limit ectopic fat accretion.PPARγ and its activators also have broad anti-inflammatory effects. On one hand, PPARγ has been shown to attenuate the expression and secretion of proinflammatory cytokines (including IL-1β and TNF-α) associated with M1 macrophages (6); on the other hand, it reduces macrophage activity via transrepression of NF-κB (7). Despite their efficacy in glycemic control and reduction of steatosis, TZDs are associated with various serious adverse side effects, including weight gain, fluid retention, osteoporosis, and cardiovascular toxicity, which have strongly limited their clinical use (4). These limitations highlight the need for novel approaches such as more selective PPARγ agonists or direct activation of downstream targets.Recently we have identified fibroblast growth factor 1 (FGF1) as a target of PPARγ in visceral adipose tissue and as a critical factor in adipose remodeling (8). Mice with an FGF1 deficiency displayed a severe diabetic phenotype with increased inflammation and fibrosis in adipose tissue. Conversely, pharmacological treatment with recombinant FGF1 (rFGF1) has a potent insulin-sensitizing effect at the systemic level, and in the liver it effectively reduces steatosis in ob/ob mice (9). It remains unclear, however, if and to what extent the hepatic effects of FGF1 are direct or indirect.In this study we used two etiologically different models of NAFLD to determine the mechanism by which rFGF1 improves liver disease: leptin-deficient ob/ob mice, which develop steatosis primarily through excessive food intake, and mice with a dietary choline deficiency, which develop steatosis primarily as a result of a defect in hepatic lipid catabolism (10). Interestingly, we found that rFGF1 effectively reverses steatosis in ob/ob mice but not in mice with a dietary choline deficiency, suggesting that rFGF1 stimulates hepatic lipid catabolism. rFGF1 treatment improved steatohepatitis and plasma alanine transaminase activity (ALT) in both models, indicating that the effects of rFGF1 on hepatic inflammation and liver function are independent of its antisteatotic properties. Together our results provide insight into the mechanism by which rFGF1 improves NAFLD and highlight its potential therapeutic value in the treatment of different aspects of liver disease.