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

Abstract

Liver regeneration after injury requires fine-tune regulation of connective tissue growth factor (Ctgf). It also involves dynamic expression of hepatocyte nuclear factor (Hnf)4α, Yes-associated protein (Yap), and transforming growth factor (Tgf)-β. The upstream inducers of Ctgf, such as Yap, etc, are well-known. However, the negative regulator of Ctgf remains unclear. Here, we investigated the Hnf4α regulation of Ctgf post-various types of liver injury. Both wild-type animals and animals contained siRNA-mediated Hnf4α knockdown and Cre-mediated Ctgf conditional deletion were used. We observed that Ctgf induction was associated with Hnf4α decline, nuclear Yap accumulation, and Tgf-β upregulation during early stage of liver regeneration. The Ctgf promoter contained an Hnf4α binding sequence that overlapped with the cis-regulatory element for Yap and Tgf-β. Ctgf loss attenuated inflammation, hepatocyte proliferation, and collagen synthesis, whereas Hnf4α knockdown enhanced Ctgf induction and liver fibrogenesis. These findings provided a new mechanism about fine-tuned regulation of Ctgf through Hnf4α antagonism of Yap and Tgf-β activities to balance regenerative and fibrotic signals.