Fibroblast growth factor 1 (FGF1) demonstrated protection against nonalcoholic fatty liver disease (NAFLD) in type 2 diabetic (T2D) and obese mice by uncertain mechanism. This study investigated the therapeutic activity and mechanism of a non-mitagenic FGF1 variant (FGF1ΔHBS) against NAFLD. FGF1ΔHBS administration was effective in 9-month old db/db mice with established NAFLD; liver weight, lipid deposition and inflammation declined and liver function improved. FGF1ΔHBS reduced oxidative stress by nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and elevation of antioxidant protein expression. FGF1ΔHBS also inhibited activity and/or expression of lipogenic genes, coincident with phosphorylation of AMP-activated protein kinase (AMPK) and its substrates. Mechanistic studies on palmitate exposed hepatic cells demonstrated that NAFLD-like oxidative damage and lipid accumulation could be reversed by FGF1ΔHBS. In palmitate treated hepatic cells, siRNA knockdown of Nrf2 abolished only FGF1ΔHBS anti-oxidative actions but not lipid metabolism improvement. In contrast, AMPK inhibition by pharmacological agents or siRNA abolished both FGF1ΔHBS benefits on oxidative stress and lipid metabolism that was FGF receptor 4 (FGFR4) dependent. Further support of these in vitro findings is that liver specific AMPK knockout abolished therapeutic effects of FGF1ΔHBS against high-fat-high-sugar diet-induced hepatic steatosis. These findings indicate that FGF1ΔHBS is effective in late stage NAFLD and acts by activation of AMPK via hepatocyte FGFR4.


Q. Lin: None. G. Cai: None. Z. Liu: None. J. Li: None. J. Li: None. K.A. Wintergerst: None. P.N. Epstein: None. L. Cai: None. Y. Li: None. Y. Tan: None.


American Diabetes Association (1-13-JF-53 to Y.T.), (1-18-IBS-082 to L.C.)

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