Phosphorylation of the nuclear receptor corepressor 1 by protein kinase B switches its corepressor targets in the liver in mice

Hepatology. 2015 Nov;62(5):1606-18. doi: 10.1002/hep.27907. Epub 2015 Jul 22.


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.

Conclusion: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • ERRalpha Estrogen-Related Receptor
  • Fatty Acids / metabolism
  • Hep G2 Cells
  • Humans
  • Insulin / pharmacology
  • Insulin Resistance
  • Liver / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Non-alcoholic Fatty Liver Disease / etiology
  • Nuclear Receptor Co-Repressor 1 / metabolism*
  • PPAR alpha / physiology
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / physiology*
  • Receptors, Estrogen / physiology


  • Fatty Acids
  • Insulin
  • Ncor1 protein, mouse
  • Nuclear Receptor Co-Repressor 1
  • PPAR alpha
  • Receptors, Estrogen
  • Proto-Oncogene Proteins c-akt