Scope: Fibroblast growth factor 21 (FGF21) participated in fish oil-mediated hepatic lipid regulation and anti-inflammatory effects in high-fat diet fed-mice. However, fish oil supplementation did not significantly increase F GF 21 protein levels. Whether fish oil-induced benefits in the liver are related to hepatic FGF21 sensitivity remains unclear. Methods and results: Male C57BL/6J mice were fed a low-fat diet (LFD), a high-fat diet (HFD) or a fish oil-supplemented high-fat diet (FOD) for 12 weeks. Fish oil improved HFDinduced hepatic steatosis and inflammation, while it exerted no obvious effect on FGF21 protein expression. FGF21 knockout studies demonstrated FGF21 participated in fish oil induced metabolic benefits. In vivo and in vitro experiments showed n-3 PUFAs, DHA and EPA, enhanced hepatic FGF21 sensitivity by increased hepatic 13-klotho expression. PPAR-gamma siRNA knockdown and PPAR-gamma antagonist (GW9662) treatment blocked the effects of DHA to enhance 13-klotho expression and FGF21 sensitivity. In addition, PPAR-gamma activation enhanced 13-klotho expression and FGF21 signaling response, illustrating PPAR-gamma participated in DHAregulated 13-klotho expression and FGF21 sensitivity. Conclusion: Our data indicate n-3 PUFAs increase hepatic FGF21 sensitivity and 13-klotho expression probably through a PPAR-gamma-dependent mechanism, and may thereby exert hepatic beneficial effects on lipid metabolism.

Fish oil; Inflammation; Lipid metabolism; Liver; Mice

Sun Yat-sen University; University of Hong Kong; Guangdong Pharmaceutical University