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Nitric oxide and TGF-beta1 inhibit HNF-4alpha function in HEPG2 cells

Susana de Lucas1, Juan Manuel López-Alcorocho, Javier Bartolomé

  • 1Fundación para el Estudio de las Hepatitis Virales, Madrid, Spain.

Biochemical and Biophysical Research Communications
|September 11, 2004
PubMed

Insights

Profibrogenic factors, transforming growth factor-beta1 (TGF-beta1) and nitric oxide, inhibit hepatocyte nuclear factor-4alpha (HNF-4alpha) activity. This mechanism, involving HNF-4alpha degradation or nitrosylation, may explain liver dysfunction during fibrosis.

Area of Science:

  • Hepatology
  • Molecular Biology
  • Cellular Signaling

Background:

  • Liver fibrosis is characterized by impaired liver function.
  • Profibrogenic factors like TGF-beta1 and nitric oxide are implicated in fibrosis progression.
  • Hepatocyte nuclear factor-4alpha (HNF-4alpha) is a key regulator of liver-specific gene expression.

Purpose of the Study:

  • To investigate the impact of TGF-beta1 and nitric oxide on HNF-4alpha function.
  • To elucidate the molecular mechanisms by which these factors affect HNF-4alpha activity.
  • To understand the role of HNF-4alpha dysfunction in liver fibrosis.

Main Methods:

  • HepG2 cells were treated with TGF-beta1 or a nitric oxide donor.
  • mRNA levels of coagulation factor VII and HNF-4alpha were quantified.
  • Chloramphenicol acetyl-transferase assays assessed factor VII gene promoter activity.
  • Gel shift assays and Western blot analyzed HNF-4alpha DNA binding and protein levels.

Main Results:

  • Both TGF-beta1 and nitric oxide downregulated factor VII mRNA.
  • This downregulation was mediated by inhibition of the factor VII gene promoter.
  • HNF-4alpha DNA binding decreased, indicating reduced HNF-4alpha activity.
  • TGF-beta1 induced HNF-4alpha degradation, while nitric oxide caused nitrosylation.

Conclusions:

  • TGF-beta1 and nitric oxide inhibit HNF-4alpha activity through distinct mechanisms.
  • Impaired HNF-4alpha function contributes to the loss of liver functions during fibrosis.
  • These findings provide insights into the molecular pathology of liver fibrosis.

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