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  11. The Reversal Of Pxr Or Pparα Activation-induced Hepatomegaly

The reversal of PXR or PPARα activation-induced hepatomegaly

Yifei Zhang1, Jie Yang1, Shicheng Fan2

  • 1Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.

Toxicology Letters
|May 11, 2024

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View abstract on PubMed

Summary
This summary is machine-generated.

Liver enlargement induced by pregnane X receptor (PXR) or peroxisome proliferator-activated receptor α (PPARα) activation is reversible. Withdrawal of agonists normalized liver size, hepatocyte characteristics, and related signaling pathways.

Area of Science:

  • Hepatology
  • Molecular Toxicology
  • Pharmacology

Background:

  • Pregnane X receptor (PXR) and peroxisome proliferator-activated receptor α (PPARα) activation can cause liver enlargement (hepatomegaly).
  • Previous studies indicated this hepatomegaly involves yes-associated protein (YAP) signaling, leading to hepatocyte hypertrophy and proliferation.
  • The reversibility of this induced hepatomegaly after agonist withdrawal was not previously established.

Purpose of the Study:

  • To investigate the regression of PXR or PPARα activation-induced hepatomegaly after the withdrawal of their respective agonists.
  • To determine if liver size, hepatocyte characteristics, and associated molecular signaling pathways return to normal levels.

Main Methods:

  • Utilized C57BL/6 mice treated with PXR agonist (PCN) or PPARα agonist (WY-14643).
Keywords:
HepatomegalyPeroxisome proliferator-activated receptor α (PPARα)Pregnane X receptor (PXR)Reversal

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  • Administered withdrawal of agonists and analyzed liver tissue using immunohistochemistry.
  • Quantified expression levels of key proteins related to PXR/PPARα signaling, hepatocyte proliferation, and YAP signaling.

    • Main Results:

    • Withdrawal of PCN or WY-14643 led to the regression of liver size to normal levels.
    • Immunohistochemistry showed a reversal of hepatocyte hypertrophy and a decrease in hepatocyte proliferation.
    • Expression of PXR/PPARα downstream targets, proliferation markers (CCNA1, CCND1, PCNA), and YAP signaling proteins (CTGF, CYR61, ANKRD1) returned to baseline levels.

    Conclusions:

    • PXR or PPARα activation-induced hepatomegaly is a reversible condition.
    • The regression involves normalization of hepatocyte size, proliferation, and YAP signaling.
    • These findings support the potential safety of PXR and PPARα as therapeutic drug targets.
    Yes-associated protein