title: Orphan nuclear receptor Nur77 mediates fasting-induced hepatic fibroblast growth factor 21 expression.
abstract: The fasting-induced hepatic hormone, fibroblast growth factor 21 (FGF21), is a potential candidate for the treatment of metabolic syndromes. Although peroxisome proliferator-activated receptor (PPAR)α is known to play a major role in the induction of hepatic FGF21 expression, other fasting-induced transcription factors that induce FGF21 expression have not yet been fully studied. In the present study, we investigated whether the fasting-induced activation of the orphan nuclear receptor Nur77 increases hepatic FGF21 expression. We found that fasting induced hepatic Nur77 and FGF21 expression. Glucagon and forskolin increased Nur77 and FGF21 expression in vivo and in vitro, respectively, and adenovirus-mediated overexpression of Nur77 (Ad-Nur77) increased FGF21 expression in vitro and in vivo. Moreover, knockdown of endogenous Nur77 expression by siRNA-Nur77 abolished the effect of forskolin on FGF21 expression. The results of ChIP assays, EMSA, and mutagenesis analysis showed that Nur77 bound to the putative NBRE of the FGF21 promoter in cultured hepatocytes and fasting induced Nur77 binding to the FGF21 promoter in vivo. Knockdown of PPARα partially inhibited forskolin-induced FGF21 expression, suggesting PPARα involvement in glucagon-stimulated FGF21 expression. In addition, double knockdown of PPARα and Nur77 further diminished FGF21 expression in cultured hepatocytes. In conclusion, this study shows that Nur77 mediates fasting-induced hepatic FGF21 expression, and suggests an alternative mechanism via which hepatic FGF21 transcription is mediated under fasting conditions.
authors.affiliation: Division of Endocrinology and Metabolism (A.-K.M., K.-H.B., Y.-K.C., M.-J.K., J.-H.K., J.-H.J., J.-G.K., I.-K.L., K.-G.P.) Department of Internal Medicine, Research Institute of Aging and Metabolism, Kyungpook National University School of Medicine, Daegu 700-721, South Korea; Division of Endocrinology and Metabolism (Y.-A.J.), Department of Internal Medicine, Keimyung University School of Medicine, Daegu 700-712, South Korea; Brain Korea 21 Plus Project for Bio-Medical Convergence Program for Creative Talent (I.-K.L.), Kyungpook National University, Daegu 702-701, South Korea.
authors.forename: Ae-Kyung
authors.initials: AK
authors.lastname: Min
authors.forename: Kwi-Hyun
authors.initials: KH
authors.lastname: Bae
authors.forename: Yun-A
authors.initials: YA
authors.lastname: Jung
authors.forename: Yeon-Kyung
authors.initials: YK
authors.lastname: Choi
authors.forename: Mi-Jin
authors.initials: MJ
authors.lastname: Kim
authors.forename: Ji-Hyun
authors.initials: JH
authors.lastname: Kim
authors.forename: Jae-Han
authors.initials: JH
authors.lastname: Jeon
authors.forename: Jung-Guk
authors.initials: JG
authors.lastname: Kim
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Lee
authors.forename: Keun-Gyu
authors.initials: KG
authors.lastname: Park
mesh_terms: D000256:Adenoviridae; D000818:Animals; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D005215:Fasting / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D005508:Food Deprivation; D005786:Gene Expression Regulation; D005934:Glucagon; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic
chemical_list: C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D005934:Glucagon; D000242:Cyclic AMP