PUBLICATION
Follistatin-controlled activin-HNF4α-coagulation factor axis in liver progenitor cells determines outcome of acute liver failure
- Authors
- Lin, T., Wang, S., Munker, S., Jung, K., Macías-Rodríguez, R.U., Ruiz-Margáin, A., Schierwagen, R., Liu, H., Shao, C., Fan, C., Feng, R., Yuan, X., Wang, S., Wandrer, F., Meyer, C., Wimmer, R., Liebe, R., Kroll, J., Zhang, L., Schiergens, T., Ten Dijke, P., Teufel, A., Marx, A., Mertens, P.R., Wang, H., Pa Ebert, M., Bantel, H., De Toni, E., Trebicka, J., Dooley, S., Shin, D., Ding, H., Weng, H.L.
- ID
- ZDB-PUB-210827-5
- Date
- 2021
- Source
- Hepatology (Baltimore, Md.) 75(2): 322-337 (Journal)
- Registered Authors
- Kroll, Jens
- Keywords
- FOXH1, TGF-β, glucagon, insulin, systemic inflammation response
- MeSH Terms
-
- Cell Line
- Activins/genetics*
- Activins/metabolism
- Liver Failure, Acute/chemically induced
- Liver Failure, Acute/metabolism*
- Liver Failure, Acute/pathology
- Liver Failure, Acute/surgery
- Stem Cells/metabolism
- Prognosis
- Forkhead Transcription Factors/genetics
- Forkhead Transcription Factors/metabolism
- Middle Aged
- Transforming Growth Factor beta1/genetics
- Aged
- Humans
- Male
- Prothrombin/genetics
- Promoter Regions, Genetic
- Prospective Studies
- Adult
- Smad4 Protein/genetics
- Blood Coagulation
- Liver Regeneration
- Signal Transduction
- Factor V/genetics
- Female
- Animals
- Follow-Up Studies
- Liver Transplantation
- Mice
- Gene Expression
- Follistatin/blood
- Follistatin/metabolism*
- Hepatocyte Nuclear Factor 4/genetics
- Hepatocyte Nuclear Factor 4/metabolism*
- Smad3 Protein/genetics
- Smad3 Protein/metabolism
- Hepatocytes/metabolism
- Zebrafish
- Acute-On-Chronic Liver Failure/blood
- Metronidazole
- Smad2 Protein/genetics
- Smad2 Protein/metabolism
- PubMed
- 34435364 Full text @ Hepatology
Citation
Lin, T., Wang, S., Munker, S., Jung, K., Macías-Rodríguez, R.U., Ruiz-Margáin, A., Schierwagen, R., Liu, H., Shao, C., Fan, C., Feng, R., Yuan, X., Wang, S., Wandrer, F., Meyer, C., Wimmer, R., Liebe, R., Kroll, J., Zhang, L., Schiergens, T., Ten Dijke, P., Teufel, A., Marx, A., Mertens, P.R., Wang, H., Pa Ebert, M., Bantel, H., De Toni, E., Trebicka, J., Dooley, S., Shin, D., Ding, H., Weng, H.L. (2021) Follistatin-controlled activin-HNF4α-coagulation factor axis in liver progenitor cells determines outcome of acute liver failure. Hepatology (Baltimore, Md.). 75(2):322-337.
Abstract
Background & aims In patients with acute liver failure (ALF) who suffer from massive hepatocyte loss, liver progenitor cells (LPC) take over key hepatocyte functions, which ultimately determines survival. This study investigated how the expression of HNF4α, its regulators and targets in LPC determines clinical outcome of ALF patients.
Approach & results Clinicopathological associations were scrutinized in 19 ALF patients (9 recovered and 10 receiving liver transplantation). Regulatory mechanisms between follistatin, activin, HNF4α and coagulation factor expression in LPC were investigated in vitro and in metronidazole-treated zebrafish. A prospective clinical study followed up 186 cirrhotic patients for 80 months to observe the relevance of follistatin levels in prevalence and mortality of acute-on-chronic liver failure (ACLF). Recovered ALF patients robustly express HNF4α in either LPC or remaining hepatocytes. As in hepatocytes, HNF4α controls the expression of coagulation factors by binding to their promoters in LPC. HNF4α expression in LPC requires the FOXH1-SMAD2/3/4 transcription factor complex, which is promoted by the TGF-β superfamily member activin. Activin signaling in LPC is negatively regulated by follistatin, a hepatocyte-derived hormone controlled by insulin and glucagon. In contrast to patients requiring liver transplantation, recovered patients demonstrate a normal activin/follistatin ratio, robust abundance of the activin effectors phosphorylated SMAD2 and HNF4α in LPC, leading to significantly improved coagulation function. A follow-up study indicated that serum follistatin levels could predict the incidence and mortality of ACLF.
Conclusions These results highlight a crucial role of the follistatin-controlled activin-HNF4α-coagulation axis in determining the clinical outcome of massive hepatocyte loss-induced ALF. The effects of insulin and glucagon on follistatin suggests a key role of the systemic metabolic state in ALF.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping