title: N-3 polyunsaturated fatty acids increase hepatic fibroblast growth factor 21 sensitivity via a PPAR-γ-β-klotho pathway.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, P. R. China.|Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, P. R. China.
authors.forename: Wenqi
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, P. R. China.|Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, P. R. China.
authors.forename: Xu
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Medicine, University of Hong Kong, Hong Kong, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, P. R. China.|Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, P. R. China.
authors.forename: Ming
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, P. R. China.|Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, P. R. China.
authors.forename: Xinwei
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, P. R. China.|Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, P. R. China.
authors.forename: Tianran
authors.initials: T
authors.lastname: Shen
authors.affiliation: Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, P. R. China.|Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, P. R. China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, P. R. China.|Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, P. R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, P. R. China.|Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, P. R. China.
authors.forename: Wenhua
authors.initials: W
authors.lastname: Ling
mesh_terms: D000818:Animals; D005230:Fatty Acids, Nonesterified / Q000097:blood; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology*; D005346:Fibroblast Growth Factors / Q000032:analysis / Q000502:physiology*; D007328:Insulin / Q000097:blood; D000090265:Klotho Proteins; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D005230:Fatty Acids, Nonesterified; D015525:Fatty Acids, Omega-3; D007328:Insulin; C418622:Klb protein, mouse; D008565:Membrane Proteins; D047495:PPAR gamma; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D000090265:Klotho Proteins
keywords: Fish oil; Inflammation; Lipid metabolism; Liver; Mice