Fibroblast Growth Factor 21 (FGF21) is a novel metabolic regulator with diverse biological functions via FGF receptors and co-receptor β-klotho . FGF21, as a hepatokine, adipokine and myokine, plays an important role in many diseases . In the aspect of regulating blood glucose, insulin sensitivity and the expression of glucose transporter1 are improved by treatment with FGF21 in diabetic mice [3, 4]. Emerging evidence indicates that FGF21 could suppress hepatic sterol regulatory element-binding protein-2 to regulate lipid metabolism and related diseases . Besides, FGF21 prevents Angiotensin Ⅱ-induced hypertension and vascular dysfunction by activation of ACE2/angiotensin (1–7) axis in mice [6, 7]. Efforts have been made to elucidate the mechanism that FGF21 regulates hepatic metabolic pathways to improve steatosis and inflammation [8, 9, 10]. Through previous studies demonstrate that FGF21 could attenuate hepatic fibrogenesis [11, 12], the therapeutic effects of FGF21 on liver fibrosis in different models and underlying mechanisms still need to be investigated.
Hepatic fibrosis is a wound healing response to varying aetiologies and as such affects the entire world population . The main causes of hepatic fibrosis include non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD) and liver cirrhosis [13, 14]. The accumulation of extracellular matrix (ECM) proteins lead to fibrous scar formation and changes of liver architecture . In the process of hepatic fibrogenesis, activation of hepatic stellate cells (HSCs), which mainly produce ECM, exhibits fibrogenic potential . Among the activating agents, transforming growth factor-β (TGF-β) and platelet-derived growth factor (PDGF) play the critical role in the regulation of activation of HSCs and the progression of fibrosis . Besides, Leptin, a 16-kDa protein hormone, plays a key role in the development of liver fibrosis, which also regulated HSC activation and ECM synthesis [18, 19]. Damaged hepatocytes release inflammatory, fibrogenic cytokines and reactive oxygen species (ROS), which could also induce the activation of HSCs [16, 20]. Liver fibrosis is a reversible process before progressing into liver cirrhosis or hepatic carcinoma [9, 14]. Therefore, developing therapeutic strategies that effectively reverse liver fibrosis are necessary for preventing the development of liver cirrhosis.
Accumulating researches demonstrate that a lot of chemicals are known to induce liver fibrosis and hence are commonly used to establish experimental animal models to study this particular pattern of lesions [21, 22]. In order to further study the therapeutic effects of FGF21 on liver fibrosis, we simulated two animal hepatic fibrosis models and one cell model, namely Carbon tetrachloride (CCL4)-induced model, Dimethylnitrosamine (DMN)-induced model and PDGF-treated HSCs model. CCL4 is the most widely used hepatotoxin in the study of liver fibrosis and cirrhosis in rodents [21, 22]. Previous studies show that lipid profile, liver enzymes and oxidative stress markers remarkably increased and high-density lipoprotein dramatically decreased in CCL4-induced model . CCL4 is metabolized by cytochrome P450 (CYP450) enzymes to a trichloromethyl radical that can be further oxygenated to the trichloromethylperoxy radical. The radicals are highly reactive and induced complex cellular alterations that result in hepatotoxic damage, inflammation fibrosis and hepatocellular carcinoma . The pathogenic mechanisms simulate human chronic disease associated with toxic damage in many aspects . DMN, an carcinogenic and genotoxic compounds, is usually used to experimentally induce hepatic fibrosis in mice [21, 24]. DMN causes activation of lymphocytes and injury to sinusoidal endothelial cells which produce potent fibrogenic factors like TGF-β1, CTGF and FGF1. Pro-inflammatory cytokines, including IL-1β, IL-6, IFN-γ and TNF-α, trigger hepatocytes to activate downstream signaling pathways such as nuclear factor-κB, which in turn induced activation of resting hepatic stellate cells [25, 26]. A number of papers have demonstrated that clusters of metabolic activation, immune response, oxidative stress metabolic disorders, ion homeostasis, HSCs activation and extracelluar matrix deposition were significantly induced in DMN model [21, 25] This model was mainly associated with potent fibrogenic factors and abundantly production of inflammation . Among the mechanisms of liver fibrogenesis, growth factor signaling and hormone play central role in the activation of HSCs, mainly through PDGF-BB  Therefore, PDGF-BB is used to activate HSCs for cell model. In this study, these three liver fibrosis models were successfully simulated. The therapeutic effects of FGF21 on liver fibrosis and the underlying mechanisms were investigated in different models.