Orphan Nuclear Receptor Nur77 Mediates Fasting-Induced Hepatic Fibroblast Growth Factor 21 Expression

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 t...

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Published in:Endocrinology (Philadelphia) 2014-08, Vol.155 (8), p.2924-2931
Main Authors: Min, Ae-Kyung, Bae, Kwi-Hyun, Jung, Yun-A, Choi, Yeon-Kyung, Kim, Mi-Jin, Kim, Ji-Hyun, Jeon, Jae-Han, Kim, Jung-Guk, Lee, In-Kyu, Park, Keun-Gyu
Format: Article
Language:English
Subjects:
Adenoviridae
Animals
Cell Line
Cyclic AMP - metabolism
Fasting - metabolism
Fibroblast Growth Factors - genetics
Fibroblast Growth Factors - metabolism
Food Deprivation
Gene Expression Regulation
Glucagon
Liver - metabolism
Male
Mice
Mice, Inbred C57BL
Nuclear Receptor Subfamily 4, Group A, Member 1 - genetics
Nuclear Receptor Subfamily 4, Group A, Member 1 - metabolism
Promoter Regions, Genetic
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Summary: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.
ISSN:0013-7227
1945-7170
DOI:10.1210/en.2013-1758