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Regulation of hepatic xenosensor function by HNF4alpha.

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Toxicological Sciences : an Official Journal of the Society of Toxicology
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Hepatocyte nuclear factor 4alpha (HNF4α) is crucial for the function of key liver xenosensors, including CAR, PXR, and PPARα. Its absence disrupts the activation of these sensors, impacting toxicological responses.

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HNF4αtranscriptional regulationxenosensor

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Area of Science:

  • Hepatology
  • Toxicology
  • Molecular Biology

Background:

  • Nuclear receptors and transcription factors like CAR, PXR, PPARα, and AhR act as critical xenobiotic sensors in the liver.
  • Hepatocyte nuclear factor 4alpha (HNF4α) is an essential orphan nuclear receptor for maintaining liver function.

Purpose of the Study:

  • To investigate the hypothesis that HNF4α is essential for the function of major hepatic xenosensors.
  • To determine the role of HNF4α in the activation and response of AhR, CAR, PXR, and PPARα.

Main Methods:

  • Utilized wild-type (WT) and hepatocyte-specific Hnf4a null (HNF4α-KO) mice.
  • Administered specific agonists for AhR (TCDD), CAR (TCPOBOP), PXR (PCN), and PPARα (WY-14643).
  • Collected blood and liver tissue to analyze receptor activation, liver-to-body weight ratio (LW/BW), and target gene expression.

Main Results:

  • AhR activation by TCDD was unaffected by HNF4α deficiency.
  • CAR, PXR, and PPARα activation, indicated by increased LW/BW ratio and target gene expression, were significantly impaired in HNF4α-KO mice compared to WT mice.
  • While PCN increased LW/BW ratio in HNF4α-KO mice, it failed to induce PXR target genes, suggesting a partial disruption.

Conclusions:

  • HNF4α is critical for the functional activation of hepatic CAR, PXR, and PPARα xenosensors.
  • The function of AhR as a xenosensor is independent of HNF4α.
  • HNF4α plays a vital role in mediating hepatic toxicological responses through xenosensor activation.