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.

Liver regeneration and ethanol detoxification: A new link in YAP regulation of ALDH1A1 during alcohol‐related hepatocyte damage

“…YAP is an important regulator in liver regeneration following chemical and surgical‐induced damage. Consistent with our recent findings, 19 this study demonstrated Yap activation upon hepatocyte damage caused by insults such as ethanol and CCl 4 . Impaired regenerative responses were observed in hepatocyte‐specific Yap1 KO as summarized in Figure 7.…”

“…Hepatocyte damage and liver regeneration were induced through combined treatment with ethanol and CCl 4 according to our previous report. 19 Animals were allowed free access to diets with increasing concentrations of ethanol to 2% vol/vol (11% of Kcal) for 4 days. A single acute dose of CCl 4 (1 μl/g body weight) prediluted 1:3 in olive oil was given through intraperitoneal injection.…”

“…25 Hnf4α was deregulated in damaged hepatocytes after ethanol/CCl 4 -induced damage. 19 To explore Yap function in regulation of hepatocyte proliferation and progenitor activation, we generated hepatocyte specific KO or controls through transduction of equal amounts of AAV8-TBG-iCre or AAV8-GFP viruses into Yap1 flox/flox homozygotes prior to moderate ethanol feeding and acute CCl 4 intoxication. Expression of iCre and GFP transgenes, and loss of Yap1 at mRNA and protein levels F I G U R E 1 YAP activation during progression of alcohol-related liver disease and in experimental models of alcohol-associated liver injury.…”

Molecular pathways of liver regeneration: A comprehensive review

“…HNF4-α is a YAP and TGF-β/SMAD3 antagonist; therefore, decreased expression of this molecule stimulates promitogenic functions and activates connective tissue growth factor. Increased HNF4-α expression during the subsequent phases of regeneration prevents the excessive synthesis of connective tissue and therefore fibrosis[ 70 ]. Hnf4-α also leads to the inhibition of HPC proliferation and migration in rats[ 71 ].…”

Pseudogene RPL32P3 regulates the blood–tumor barrier permeability via the YBX2/HNF4G axis

“…As nuclear receptor transcription factors, HNF4 can directly regulate the transcription of the target gene by combining with the target gene promoter. HNF4α negatively regulated the transcription of CTGF by binding to its promoter during hepatocyte regeneration [ 39 ]. HNF4G activated the transcription of HAS2 by interacting with the promoter/enhancer region of HAS2 to promote the growth and invasion of bladder cancer cells [ 40 ].…”