title: Phosphorylation of the nuclear receptor corepressor 1 by protein kinase B switches its corepressor targets in the liver in mice.
abstract: Nuclear receptor corepressor 1 (NCoR1) is a transcriptional coregulator that has wide-ranging effects on gene expression patterns. In the liver, NCoR1 represses lipid synthesis in the fasting state, whereas it inhibits activation of peroxisome proliferator-activated receptor alpha (PPARα) upon feeding, thereby blunting ketogenesis. Here, we show that insulin by activation of protein kinase B induces phosphorylation of NCoR1 on serine 1460, which selectively favors its interaction with PPARα and estrogen-related receptor alpha (ERRα) over liver X receptor alpha (LXRα). Phosphorylation of NCoR1 on S1460 selectively derepresses LXRα target genes, resulting in increased lipogenesis, whereas, at the same time, it inhibits PPARα and ERRα targets, thereby attenuating oxidative metabolism in the liver. Phosphorylation-gated differential recruitment of NCoR1 to different nuclear receptors explains the apparent paradox that liver-specific deletion of NCoR1 concurrently induces both lipogenesis and oxidative metabolism owing to a global derepression of LXRα, PPARα, and ERRα activity.
  
  
  CONCLUSIONS
  Phosphorylation-mediated recruitment switch of NCoR1 between nuclear receptor subsets provides a mechanism by which corepressors can selectively modulate liver energy metabolism during the fasting-feeding transition.
authors.affiliation: Laboratory of Integrative and Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.|Division of Endocrinology, Department of Internal Medicine, Open NBI Convergence Technology Research Laboratory, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Young Suk
authors.initials: YS
authors.lastname: Jo
authors.affiliation: Laboratory of Integrative and Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Dongryeol
authors.initials: D
authors.lastname: Ryu
authors.affiliation: Laboratory of Integrative and Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Adriano
authors.initials: A
authors.lastname: Maida
authors.affiliation: Laboratory of Integrative and Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Gene Expression Laboratory, Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA.
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Evans
authors.affiliation: Metabolic Signaling, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Kristina
authors.initials: K
authors.lastname: Schoonjans
authors.affiliation: Laboratory of Integrative and Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
mesh_terms: D000818:Animals; D005227:Fatty Acids / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology; D056971:Nuclear Receptor Co-Repressor 1 / Q000378:metabolism*; D047493:PPAR alpha / Q000502:physiology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D011960:Receptors, Estrogen / Q000502:physiology; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D005227:Fatty Acids; D007328:Insulin; D056971:Nuclear Receptor Co-Repressor 1; D047493:PPAR alpha; D051057:Proto-Oncogene Proteins c-akt; D011960:Receptors, Estrogen; D000097983:ERRalpha Estrogen-Related Receptor; C539128:Ncor1 protein, mouse