Fasting-induced FGF21 is repressed by LXR activation via recruitment of an HDAC3 corepressor complex in mice.
The liver plays a pivotal role in the physiological adaptation to fasting and a better understanding of the metabolic adaptive responses may give hints on new therapeutic strategies to control the metabolic diseases. The liver X receptors (LXRs) are well-established regulators of lipid and glucose metabolism. More recently fibroblast growth factor 21 (FGF21) has emerged as an important regulator of energy homeostasis. We hypothesized that the LXR transcription factors could influence Fgf21 expression, which is induced in response to fasting. Wild-type, LXRα(-/-), and LXRβ(-/-) mice were treated for 3 d with vehicle or the LXR agonist GW3965 and fasted for 12 h prior to the killing of the animals. Interestingly, serum FGF21 levels were induced after fasting, but this increase was blunted when the mice were treated with GW3965 independently of genotypes. Compared with wild-type mice, GW3965-treated LXRα(-/-) and LXRβ(-/-) mice showed improved insulin sensitivity and enhanced ketogenic response at fasting. Of note is that during fasting, GW3965 treatment tended to reduce liver triglycerides as opposed to the effect of the agonist in the fed state. The LXR-dependent repression of Fgf21 seems to be mainly mediated by the recruitment of LXRβ onto the Fgf21 promoter upon GW3965 treatment. This repression by LXRβ occurs through the recruitment and stabilization of the repressor complex composed of retinoid-related orphan receptor-α/Rev-Erbα/histone deacetylase 3 onto the Fgf21 promoter. Our data clearly demonstrate that there is a cross talk between the LXR and FGF21 signaling pathways in the adaptive response to fasting.
Department of Biosciences and Nutrition and Center for Biosciences at Novum, Karolinska Institute, S-141 83 Huddinge, Sweden.
Amena
A
Archer
Nicolas
N
Venteclef
Agneta
A
Mode
Matteo
M
Pedrelli
Chiara
C
Gabbi
Karine
K
Clément
Paolo
P
Parini
Jan-Åke
JÅ
Gustafsson
Marion
M
Korach-André
D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D005215:Fasting / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000097:blood / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism*; D006706:Homeostasis; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008099:Liver; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000378:metabolism; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D015398:Signal Transduction; D014280:Triglycerides / Q000378:metabolism; D000099186:Histone Deacetylase 3
D001565:Benzoates; D001596:Benzylamines; D005346:Fibroblast Growth Factors; D005947:Glucose; D006655:Histone Deacetylases; D000071518:Liver X Receptors; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D057093:Orphan Nuclear Receptors; D014280:Triglycerides; D000099186:Histone Deacetylase 3; C473027:GW 3965; C498262:Nr1d1 protein, mouse; C000605214:Nr1h3 protein, mouse; C414620:fibroblast growth factor 21