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Hepatocyte nuclear factor 4α negatively regulates connective tissue growth factor during liver regeneration
Author(s) -
Zhou Junmei,
Sun Xiaowei,
Yang Lu,
Wang Liqun,
Ran Gai,
Wang Jinhui,
Cao Qi,
Wu Lizi,
Bryant Andrew,
Ling Chen,
Pi Liya
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201902382r
Subject(s) - ctgf , hepatocyte nuclear factor 4 , growth factor , gene knockdown , hepatocyte , hepatocyte nuclear factors , connective tissue , microbiology and biotechnology , liver regeneration , transforming growth factor , transforming growth factor beta , hepatocyte growth factor , biology , regeneration (biology) , chemistry , endocrinology , transcription factor , nuclear receptor , genetics , cell culture , gene , receptor , in vitro
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.