Hepatocyte nuclear factor 4α negatively regulates connective tissue growth factor during liver regeneration.
FASEB J
; 34(4): 4970-4983, 2020 04.
Article
em En
| MEDLINE
| ID: mdl-32057145
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)-ß. 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-ß 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-ß. 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-ß activities to balance regenerative and fibrotic signals.
Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Hepatócitos
/
Fator 4 Nuclear de Hepatócito
/
Fator de Crescimento do Tecido Conjuntivo
/
Regeneração Hepática
Limite:
Animals
/
Humans
Idioma:
En
Revista:
FASEB J
Assunto da revista:
BIOLOGIA
/
FISIOLOGIA
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Estados Unidos