Activating AMP-activated Protein Kinase Mediates Fibroblast Growth Factor 1 Protection from Nonalcoholic Fatty Liver Disease in Mice

BACKGROUND AND AIMS: Fibroblast growth factor 1 (FGF1) demonstrated protection against nonalcoholic fatty liver disease (NAFLD) in type 2 diabetic and obese mice by an uncertain mechanism. This study investigated the therapeutic activity and mechanism of a non-mitogenic FGF1 variant (FGF1(ΔHBS)) against NAFLD. APPROACH AND RESULTS: FGF1(ΔHBS) administration was effective in 9-month old db/db mice with NAFLD; liver weight, lipid deposition and inflammation declined and liver injury decreased. FGF1(ΔHBS) reduced oxidative stress by stimulating nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and elevation of antioxidant protein expression. FGF1(ΔHBS) 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 FGF1(ΔHBS). In palmitate-treated hepatic cells, siRNA knockdown of Nrf2 abolished only FGF1(ΔHBS) anti-oxidative actions but not improvement of lipid metabolism. In contrast, AMPK inhibition by pharmacological agent or siRNA abolished FGF1(ΔHBS) benefits on both oxidative stress and lipid metabolism that were FGF receptor 4 (FGFR4) dependent. Further support of these in vitro findings is that liver-specific AMPK knockout abolished therapeutic effects of FGF1(ΔHBS) against high-fat/high-sucrose diet-induced hepatic steatosis. Moreover, FGF1(ΔHBS) improved high-fat/high-cholesterol diet-induced steatohepatitis and fibrosis in apolipoprotein E knockout mice. CONCLUSIONS: These findings indicate that FGF1(ΔHBS) is effective for preventing and reversing liver steatosis and steatohepatitis and acts by activation of AMPK via hepatocyte FGFR4.