Severe hypoxia specifically downregulates hepatocyte nuclear factor-4 geneexpression in HepG2 human hepatoma cells

The liver is one of the organs in which hypoxia helps to regulate gene expr ession under normal physiological conditions and in diseases such as cirrho sis and cancer. We postulated that the expression/activity of some of the ' liver-enriched' transcription factors, which control liver-specific genes, was sensitive to hypoxia. We tested hepatocyte nuclear factor-1 (HNF-1), HN F-3 and HNF-4, which play key roles in differentiation, development and hep atic gene expression, using HepG2 human hepatoma cells cultured under hypox ic conditions. Severe hypoxia/ anoxia downregulated HNF-4 DNA-binding activ ity while DNA-binding activity of HNF-1 and HNF-3 remained unaffected. Thes e hypoxic conditions also strongly and specifically decreased cell contents of HNF-4 protein, indicating that the decrease in HNF-4 DNA-binding activi ty was due to the lower amount of protein and not to decreased DNA-binding affinity. Northern analysis indicated that the expression of the hnf-4 gene was also downregulated in HepG2 cells cultured under hypoxic conditions. T hese results provide evidence that hypoxic stress triggers a cascade of eve nts that inhibits the trans-activation potential of HNF-4 in HepG2 cells. T his step may be crucial in modulating the expression of a subset of liver g enes that are targets for this nuclear receptor. This relationship provides a new route for the investigation of the effects of hypoxia on the liver c ell. Copyright (C) 2001 S.KargerAG, Basel.