N‐3 Polyunsaturated Fatty Acids Increase Hepatic Fibroblast Growth Factor 21 Sensitivity Through PPARγ‐β‐klotho Pathway

Abstract

ObjectiveFibroblast growth factor 21 (FGF21) is an important physiological metabolic regulator with diverse functions in lipid and glucose metabolism. However, circulating FGF21 levels were elevated in obesity, nonalcoholic fatty liver disease (NAFLD) and atherosclerosis, which is also demonstrated in our previous study that elevated FGF21 levels were associated with dyslipidemia and insulin resistance. Paradoxically increased FGF21 levels in metabolic disorders indicate impaired FGF21 sensitivity or occurrence of FGF21 resistance. In the present study, we found that FGF21 was involved in fish oil‐mediated hepatic lipid‐regulating and anti‐inflammatory effects in mice fed with high fat diet. However, fish oil supplementation did not significantly increase hepatic and circulating FGF21 protein levels. Whether fish oil feeding‐induced benefits in liver are related to hepatic FGF21 sensitivity remains unclear and needs further investigation.MethodsTo determine the effects of n‐3 polyunsaturated fatty acids (PUFAs) on FGF21 sensitivity, we examined the response to acute FGF21 administration in vivo and in vitro.ResultsMale 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 exerted no obvious effect on FGF21 protein expression. Nevertheless, FGF21 knockout studies demonstrated that FGF21 participated in fish oil‐induced metabolic benefits. Then the FGF21 signaling pathway of n‐3 PUFAs‐induced improvement in lipid metabolism were examined. In vivo and in vitro experiments showed that n‐3 PUFAs, DHA and EPA, promoted hepatic FGF21 signal transduction and enhanced FGF21‐induced changes in serum insulin and NEFA. N‐3 PUFAs‐mediated elevated hepatic FGF21 sensitivity was probably due to increased hepatic β‐klotho expression. Furthermore, PPARγ siRNA knockdown and PPARγ selective antagonist GW9662 treatment blocked the effects of DHA to enhance β‐klotho expression and FGF21 signaling, illustrating that PPARγ participated in DHA‐regulated β‐klotho expression and FGF21 sensitivity.ConclusionOur data indicate that n‐3 PUFAs increase hepatic FGF21 sensitivity and β‐klotho expression probably through a PPARγ dependent mechanism, and may thereby exert hepatic beneficial effects on lipid metabolism and inflammation.Support or Funding InformationThis work was supported by grants from the National Research Program of China (973 Program, 2012CB517506).