Hepatocyte nuclear factor 4α negatively regulates connective tissue growth factor during liver regeneration

Area of Science:

• Molecular biology
• Hepatology
• Regenerative medicine

Background:

• Liver regeneration requires precise control of connective tissue growth factor (Ctgf).
• Key regulators like hepatocyte nuclear factor (Hnf)4α, Yes-associated protein (Yap), and transforming growth factor (Tgf)-β are dynamically expressed.
• While Ctgf inducers are known, its negative regulator remains unidentified.

Purpose of the Study:

• To investigate the role of Hnf4α in regulating Ctgf following liver injury.
• To elucidate the mechanism by which Hnf4α controls Ctgf expression and its impact on liver regeneration and fibrosis.

Main Methods:

• Utilized wild-type animals, siRNA-mediated Hnf4α knockdown models, and Cre-mediated Ctgf conditional deletion models.
• Analyzed Ctgf, Hnf4α, Yap, and Tgf-β expression during early liver regeneration.
• Performed promoter analysis to identify Hnf4α binding sites overlapping with Yap and Tgf-β regulatory elements.

Main Results:

• Ctgf induction correlated with decreased Hnf4α, increased nuclear Yap, and elevated Tgf-β during early liver regeneration.
• Hnf4α binding sequences on the Ctgf promoter overlapped with cis-regulatory elements for Yap and Tgf-β.
• Ctgf deficiency reduced inflammation, hepatocyte proliferation, and collagen synthesis; Hnf4α knockdown exacerbated Ctgf induction and liver fibrogenesis.

Conclusions:

• Hnf4α acts as a negative regulator of Ctgf in the injured liver.
• Hnf4α antagonizes Yap and Tgf-β activities, providing a mechanism for fine-tuning Ctgf.
• This regulation is crucial for balancing regenerative and fibrotic signaling pathways in the liver.