N-3 polyunsaturated fatty acids increase hepatic fibroblast growth factor 21 sensitivity via a PPAR-γ-β-klotho pathway.

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 FGF21 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 HFD-induced 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 β-klotho expression. PPAR-γ siRNA knockdown and PPAR-γ antagonist (GW9662) treatment blocked the effects of DHA to enhance β-klotho expression and FGF21 sensitivity. In addition, PPAR-γ activation enhanced β-klotho expression and FGF21 signaling response, illustrating PPAR-γ participated in DHA-regulated β-klotho expression and FGF21 sensitivity.

CONCLUSION: Our data indicate n-3 PUFAs increase hepatic FGF21 sensitivity and β-klotho expression probably through a PPAR-γ-dependent mechanism, and may thereby exert hepatic beneficial effects on lipid metabolism.