Retinoic acid receptor-related orphan receptor (ROR) alpha4 is the predominant isoform of the nuclear receptor RORalpha in the liver and is up-regulated by hypoxia in HepG2 human hepatoma cells

Biochem J. 2002 Jun 1;364(Pt 2):449-56. doi: 10.1042/BJ20011558.


The retinoic acid receptor-related orphan receptor alpha (RORalpha) is critically involved in many physiological functions in several organs. We find that the main RORalpha isoform in the mouse liver is the RORalpha4 isoform, in terms of both mRNA and protein levels, while the RORalpha1 isoform is less abundant. Because hypoxia is a major feature of liver physiology and pathology, we examined the effect of this stress on Rora gene expression and RORalpha transcriptional activity. HepG2 human hepatoma cells were cultured for 24 h under normoxia (20% O2) or hypoxia (10, 2, and 0.1% O2) and the abundance of the Rora transcripts measured by Northern blot and semi-quantitative RT-PCR. Hypoxic HepG2 cells contained more Rora mRNA than controls. This was also observed in rat hepatocytes in primary culture. Cobalt chloride and desferrioxamine also increased the amount of Rora mRNA in HepG2 cells. It is likely that these treatments increase the amount of the RORalpha4 protein in HepG2 cells as evidenced by Western blotting in the case of desferrioxamine. Transient transfection experiments indicated that hypoxia, cobalt chloride, and desferrioxamine all stimulate RORalpha transcriptional activity in HepG2 cells. Hence, we believe that RORalpha participates in the control of gene transcription in hepatic cells and modulates gene expression in response to hypoxic stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / pathology
  • Cell Hypoxia*
  • Cobalt / pharmacology
  • DNA Primers
  • Deferoxamine / pharmacology
  • Gene Expression Regulation / drug effects
  • Humans
  • Liver / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Nuclear Receptor Subfamily 1, Group F, Member 1
  • Rats
  • Rats, Wistar
  • Receptor Protein-Tyrosine Kinases
  • Receptor Tyrosine Kinase-like Orphan Receptors
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Receptors, Cytoplasmic and Nuclear
  • Reverse Transcriptase Polymerase Chain Reaction
  • Trans-Activators
  • Transcription, Genetic / drug effects
  • Tumor Cells, Cultured
  • Up-Regulation*


  • DNA Primers
  • Nuclear Receptor Subfamily 1, Group F, Member 1
  • RORA protein, human
  • Receptors, Cell Surface
  • Receptors, Cytoplasmic and Nuclear
  • Rora protein, mouse
  • Trans-Activators
  • Cobalt
  • ROR1 protein, human
  • Receptor Protein-Tyrosine Kinases
  • Receptor Tyrosine Kinase-like Orphan Receptors
  • cobaltous chloride
  • Deferoxamine