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Underexpressed coactivators PGC1alpha and SRC1 impair hepatocyte nuclear factor 4 alpha function and promote

Celia P Martínez-Jiménez1, M José Gómez-Lechón, José V Castell

  • 1Unidad de Hepatología Experimental, Centro de Investigación, Hospital Universitario La Fe, 46009 Valencia, Spain.

The Journal of Biological Chemistry
|August 8, 2006
PubMed

Insights

Hepatocyte nuclear factor 4alpha (HNF4alpha) function in liver cells relies on coactivators like PGC1alpha and SRC1. Their reduced expression in hepatomas impairs HNF4alpha activity, affecting liver gene regulation and cell differentiation.

Area of Science:

  • Molecular Biology
  • Hepatology
  • Gene Regulation

Background:

  • Hepatocyte nuclear factor 4alpha (HNF4alpha) is crucial for liver development and gene transcription in adult livers.
  • In human hepatoma HepG2 cells, HNF4alpha shows high expression but low activity on target genes.
  • This functional deficit is linked to reduced expression of essential coactivators.

Purpose of the Study:

  • To investigate the role of coactivators in HNF4alpha activity in human hepatoma cells.
  • To determine the impact of coactivator expression on HNF4alpha-dependent gene regulation and cell phenotype.
  • To explore the effect of insulin on coactivator expression and HNF4alpha target genes.

Main Methods:

  • Reporter assays using an Apo-CIII promoter construct to identify key HNF4alpha coactivators.
  • Analysis of coactivator expression in human hepatoma samples.
  • Overexpression of coactivators (SRC1, PGC1alpha) using recombinant adenoviruses in HepG2 cells.
  • Measurement of HNF4alpha-dependent gene expression and ureogenic rate.
  • Insulin treatment of human hepatocytes and HepG2 cells.

Main Results:

  • PGC1alpha and SRC1 were identified as critical HNF4alpha coactivators.
  • Expression of PGC1alpha and SRC1 is downregulated in human hepatomas.
  • Overexpression of PGC1alpha and SRC1 restored HNF4alpha activity, upregulating target genes and promoting cell differentiation.
  • Insulin repressed PGC1alpha expression and downregulated HNF4alpha target genes.

Conclusions:

  • SRC1 and particularly PGC1alpha are essential coactivators for HNF4alpha function in the human liver.
  • These coactivators play a key role in the integrated control of hepatic genes involved in metabolism and homeostasis.
  • Downregulation of HNF4alpha coactivators may contribute to hepatoma dedifferentiation.

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