Glycerol kinase enhances hepatic lipid metabolism by repressing nuclear receptor subfamily 4 group A1 in the nucleus

Biochem Cell Biol. 2020 Jun;98(3):370-377. doi: 10.1139/bcb-2019-0317. Epub 2019 Dec 7.


Glycerol kinase (GYK) plays a critical role in hepatic metabolism by converting glycerol to glycerol 3-phosphate in an ATP-dependent reaction. GYK isoform b is the only glycerol kinase present in whole cells, and has a non-enzymatic moonlighting function in the nucleus. GYK isoform b acts as a co-regulator of nuclear receptor subfamily 4 group A1 (NR4A1) and participates in the regulation of hepatic glucose metabolism by protein-protein interaction with NR4A1. Herein, GYK expression was found to upregulate the expression of NR4A1-mediated lipid metabolism-related genes (SREBP1C, FASN, ACACA, and GPAM) in HEK293T and L02 cells, and in mouse in vivo studies. GYK expression increased blood levels of cholesterol, triglyceride, and high-density lipoprotein cholesterol, but not low-density lipoprotein cholesterol levels. It enhanced the transcriptional activity of Nr4a1 target genes by negatively cooperating with NR4A1 and its enzymatic activity or by other undefined moonlighting functions. This enhancement was observed in both normal and diabetic mice. We also found a feed-forward regulation loop between GYK and NR4A1, serving as part of a GYK-NR4A1 regulatory mechanism in hepatic metabolism. Thus, GYK regulates the effect of NR4A1 on hepatic lipid metabolism in normal and diabetic mice, partially through the cooperation of GYK and NR4A1.

Keywords: NR4A1; diabetes; diabète; feed-forward regulation; glycerol kinase; glycérol kinase; lipid metabolism; métabolisme des lipides; régulation ouverte.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Nucleus / metabolism
  • Diabetes Mellitus, Experimental / metabolism
  • Gene Expression Regulation*
  • Glucose / metabolism
  • Glycerol Kinase / metabolism*
  • HEK293 Cells
  • Homeostasis
  • Humans
  • Ligands
  • Lipid Metabolism*
  • Liver / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / metabolism*
  • Protein Isoforms
  • Triglycerides / metabolism
  • Up-Regulation


  • Ligands
  • NR4A1 protein, human
  • Nr4a1 protein, mouse
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Protein Isoforms
  • Triglycerides
  • Glycerol Kinase
  • Glucose