HNF4α improves hepatocyte regeneration by upregulating PXR

Area of Science:

• Hepatology
• Molecular Biology
• Cellular Biology

Background:

• Hepatocyte nuclear factor 4 alpha (HNF4α) and pregnane X receptor (PXR) are crucial for hepatocyte regeneration.
• The precise regulatory role of HNF4α in PXR-mediated liver regeneration remains unclear.

Purpose of the Study:

• To investigate the regulatory relationship between HNF4α and PXR.
• To determine if HNF4α influences hepatocyte regeneration via PXR modulation.

Main Methods:

• Constructed a mouse PXR gene reporter and HNF4α overexpression plasmid for transfection into mouse hepatoma cells (Hepa1-6).
• Assessed PXR gene reporter fluorescence, PXR gene, and protein expression levels.
• Analyzed apoptosis and cell cycle progression to evaluate hepatocyte regeneration.
• Utilized ketoconazole to inhibit PXR expression and performed partial hepatectomy (PHx) in mice with HNF4α inhibition.

Main Results:

• Overexpression of HNF4α significantly increased PXR reporter activity, gene, and protein expression, indicating HNF4α upregulates PXR.
• Increased HNF4α and PXR expression correlated with decreased apoptosis and increased hepatocyte proliferation.
• Inhibition of PXR by ketoconazole reduced proliferation rates.
• In vivo studies demonstrated that HNF4α upregulates PXR to promote liver regeneration following partial hepatectomy.

Conclusions:

• Hepatocyte nuclear factor 4 alpha (HNF4α) promotes hepatocyte regeneration by upregulating the pregnane X receptor (PXR).
• This regulatory axis offers potential therapeutic targets for liver injury treatment.