PMID- 34435364
OWN - NLM
STAT- MEDLINE
DCOM- 20220301
LR  - 20230309
IS  - 1527-3350 (Electronic)
IS  - 0270-9139 (Linking)
VI  - 75
IP  - 2
DP  - 2022 Feb
TI  - Follistatin-controlled activin-HNF4alpha-coagulation factor axis in liver progenitor 
      cells determines outcome of acute liver failure.
PG  - 322-337
LID - 10.1002/hep.32119 [doi]
AB  - BACKGROUND AND AIMS: In patients with acute liver failure (ALF) who suffer from 
      massive hepatocyte loss, liver progenitor cells (LPCs) take over key hepatocyte 
      functions, which ultimately determines survival. This study investigated how the 
      expression of hepatocyte nuclear factor 4alpha (HNF4alpha), its regulators, and targets 
      in LPCs determines clinical outcome of patients with ALF. APPROACH AND RESULTS: 
      Clinicopathological associations were scrutinized in 19 patients with ALF (9 
      recovered and 10 receiving liver transplantation). Regulatory mechanisms between 
      follistatin, activin, HNF4alpha, and coagulation factor expression in LPC were 
      investigated in vitro and in metronidazole-treated zebrafish. A prospective 
      clinical study followed up 186 patients with cirrhosis for 80 months to observe 
      the relevance of follistatin levels in prevalence and mortality of 
      acute-on-chronic liver failure. Recovered patients with ALF robustly express 
      HNF4alpha in either LPCs or remaining hepatocytes. As in hepatocytes, HNF4alpha controls 
      the expression of coagulation factors by binding to their promoters in LPC. HNF4alpha 
      expression in LPCs requires the forkhead box protein H1-Sma and Mad homolog 2/3/4 
      transcription factor complex, which is promoted by the TGF-beta superfamily member 
      activin. Activin signaling in LPCs 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 Sma and Mad homolog 2 and HNF4alpha in LPCs, leading to significantly 
      improved coagulation function. A follow-up study indicated that serum follistatin 
      levels could predict the incidence and mortality of acute-on-chronic liver 
      failure. CONCLUSIONS: These results highlight a crucial role of the 
      follistatin-controlled activin-HNF4alpha-coagulation axis in determining the clinical 
      outcome of massive hepatocyte loss-induced ALF. The effects of insulin and 
      glucagon on follistatin suggest a key role of the systemic metabolic state in 
      ALF.
CI  - (c) 2021 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of 
      American Association for the Study of Liver Diseases.
FAU - Lin, Tao
AU  - Lin T
AD  - Department of Medicine II, Section Molecular Hepatology, University Medical 
      Center Mannheim, Medical Faculty MannheimHeidelberg UniversityMannheimGermany.
FAU - Wang, Shanshan
AU  - Wang S
AD  - Department of Medicine II, Section Molecular Hepatology, University Medical 
      Center Mannheim, Medical Faculty MannheimHeidelberg UniversityMannheimGermany.
AD  - Beijing Institute of HepatologyBeijing You'an HospitalCapital Medical 
      UniversityBeijingChina.
FAU - Munker, Stefan
AU  - Munker S
AD  - Department of Medicine IIUniversity Hospital, Campus Grosshadern, LMU 
      MunichMunichGermany.
FAU - Jung, Kyounghwa
AU  - Jung K
AD  - Department of Developmental BiologyMcGowan Institute for Regenerative 
      MedicineUniversity of PittsburghPittsburghPennsylvaniaUSA.
FAU - Macias-Rodriguez, Ricardo U
AU  - Macias-Rodriguez RU
AUID- ORCID: 0000-0002-7637-4477
AD  - Department of GastroenterologyInstituto Nacional de Ciencias Medicas y Nutricion 
      Salvador ZubiranMexico cityMexico.
FAU - Ruiz-Margain, Astrid
AU  - Ruiz-Margain A
AD  - Department of GastroenterologyInstituto Nacional de Ciencias Medicas y Nutricion 
      Salvador ZubiranMexico cityMexico.
FAU - Schierwagen, Robert
AU  - Schierwagen R
AD  - Translational Hepatology, Medical Department IFrankfurt University 
      HospitalFrankfurtGermany.
FAU - Liu, Hui
AU  - Liu H
AD  - Department of PathologyBeijing You'an HospitalAffiliated with Capital Medical 
      UniversityBeijingChina.
FAU - Shao, Chen
AU  - Shao C
AD  - Department of PathologyBeijing You'an HospitalAffiliated with Capital Medical 
      UniversityBeijingChina.
FAU - Fan, Chunlei
AU  - Fan C
AD  - Department of Gastroenterology and HepatologyBeijing You'an HospitalAffiliated 
      with Capital Medical UniversityBeijingChina.
FAU - Feng, Rilu
AU  - Feng R
AD  - Department of Medicine II, Section Molecular Hepatology, University Medical 
      Center Mannheim, Medical Faculty MannheimHeidelberg UniversityMannheimGermany.
FAU - Yuan, Xiaodong
AU  - Yuan X
AD  - Department of Medicine II, Section Molecular Hepatology, University Medical 
      Center Mannheim, Medical Faculty MannheimHeidelberg UniversityMannheimGermany.
FAU - Wang, Sai
AU  - Wang S
AD  - Department of Medicine II, Section Molecular Hepatology, University Medical 
      Center Mannheim, Medical Faculty MannheimHeidelberg UniversityMannheimGermany.
FAU - Wandrer, Franziska
AU  - Wandrer F
AD  - Department of Gastroenterology, Hepatology and EndocrinologyHannover Medical 
      SchoolHannoverGermany.
FAU - Meyer, Christoph
AU  - Meyer C
AD  - Department of Medicine II, Section Molecular Hepatology, University Medical 
      Center Mannheim, Medical Faculty MannheimHeidelberg UniversityMannheimGermany.
FAU - Wimmer, Ralf
AU  - Wimmer R
AD  - Department of Medicine IIUniversity Hospital, Campus Grosshadern, LMU 
      MunichMunichGermany.
FAU - Liebe, Roman
AU  - Liebe R
AD  - Clinic of Gastroenterology, Hepatology and Infectious DiseasesHeinrich Heine 
      UniversityDusseldorfGermany.
AD  - Department of Medicine IISaarland University Medical CenterSaarland 
      UniversityHomburgGermany.
FAU - Kroll, Jens
AU  - Kroll J
AD  - Vascular Biology and Tumor AngiogenesisEuropean Center for AngioscienceMedical 
      Faculty MannheimHeidelberg UniversityMannheimGermany.
FAU - Zhang, Long
AU  - Zhang L
AD  - Life Sciences Institute and Innovation Center for Cell Signaling 
      NetworkHangzhouChina.
FAU - Schiergens, Tobias
AU  - Schiergens T
AD  - Department of General, Visceral, Transplantation, Vascular and Thoracic 
      SurgeryUniversity HospitalLMU MunichMunichGermany.
FAU - Ten Dijke, Peter
AU  - Ten Dijke P
AD  - Oncode Institute and Department of Cell and Chemical BiologyLeiden University 
      Medical CenterLeidenThe Netherlands.
FAU - Teufel, Andreas
AU  - Teufel A
AD  - Division of Hepatology, Division of Clinical Bioinformatics, Department of 
      Medicine II, University Medical Center Mannheim, Medical Faculty 
      MannheimHeidelberg UniversityMannheimGermany.
AD  - Clinical Cooperation Unit Healthy MetabolismCenter for Preventive Medicine and 
      Digital Health Baden-WurttembergMedical Faculty MannheimHeidelberg 
      UniversityMannheimGermany.
FAU - Marx, Alexander
AU  - Marx A
AD  - Institute of PathologyUniversity Medical Center MannheimHeidelberg 
      UniversityMannheimGermany.
FAU - Mertens, Peter R
AU  - Mertens PR
AD  - Clinic of Nephrology and Hypertension, Diabetes and 
      EndocrinologyOtto-von-Guericke-UniversityMagdeburgGermany.
FAU - Wang, Hua
AU  - Wang H
AD  - Department of Oncologythe First Affiliated Hospital of Anhui Medical 
      UniversityHefeiChina.
AD  - Inflammation and Immune Mediated Disease Laboratory of Anhui ProvinceHefeiChina.
FAU - Ebert, Matthias P A
AU  - Ebert MPA
AD  - Mannheim Institute for Innate ImmunoscienceMannheimGermany.
AD  - Clinical Cooperation Unit Healthy MetabolismCenter of Preventive Medicine and 
      Digital HealthMedical Faculty MannheimHeidelberg UniversityMannheimGermany.
AD  - Department of Medicine II, University Medical Center Mannheim, Medical Faculty 
      MannheimHeidelberg UniversityMannheimGermany.
FAU - Bantel, Heike
AU  - Bantel H
AD  - Department of Gastroenterology, Hepatology and EndocrinologyHannover Medical 
      SchoolHannoverGermany.
FAU - N De Toni, Enrico
AU  - N De Toni E
AD  - Department of Medicine IIUniversity Hospital, Campus Grosshadern, LMU 
      MunichMunichGermany.
FAU - Trebicka, Jonel
AU  - Trebicka J
AUID- ORCID: 0000-0002-7028-3881
AD  - Translational Hepatology, Medical Department IFrankfurt University 
      HospitalFrankfurtGermany.
AD  - European Foundation for Study of Chronic Liver FailureBarcelonaSpain.
FAU - Dooley, Steven
AU  - Dooley S
AD  - Department of Medicine II, Section Molecular Hepatology, University Medical 
      Center Mannheim, Medical Faculty MannheimHeidelberg UniversityMannheimGermany.
FAU - Shin, Donghun
AU  - Shin D
AD  - Department of Developmental BiologyMcGowan Institute for Regenerative 
      MedicineUniversity of PittsburghPittsburghPennsylvaniaUSA.
FAU - Ding, Huiguo
AU  - Ding H
AD  - Department of Gastroenterology and HepatologyBeijing You'an HospitalAffiliated 
      with Capital Medical UniversityBeijingChina.
FAU - Weng, Hong-Lei
AU  - Weng HL
AD  - Department of Medicine II, Section Molecular Hepatology, University Medical 
      Center Mannheim, Medical Faculty MannheimHeidelberg UniversityMannheimGermany.
LA  - eng
GR  - R01 DK101426/GF/NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20211214
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (FOXH1 protein, human)
RN  - 0 (Follistatin)
RN  - 0 (Forkhead Transcription Factors)
RN  - 0 (HNF4A protein, human)
RN  - 0 (Hepatocyte Nuclear Factor 4)
RN  - 0 (SMAD2 protein, human)
RN  - 0 (SMAD3 protein, human)
RN  - 0 (SMAD4 protein, human)
RN  - 0 (Smad2 Protein)
RN  - 0 (Smad3 Protein)
RN  - 0 (Smad4 Protein)
RN  - 0 (TGFB1 protein, human)
RN  - 0 (Transforming Growth Factor beta1)
RN  - 0 (activin A)
RN  - 104625-48-1 (Activins)
RN  - 140QMO216E (Metronidazole)
RN  - 9001-24-5 (Factor V)
RN  - 9001-26-7 (Prothrombin)
SB  - IM
MH  - Activins/*genetics/metabolism
MH  - Acute-On-Chronic Liver Failure/blood
MH  - Adult
MH  - Aged
MH  - Animals
MH  - Blood Coagulation
MH  - Cell Line
MH  - Factor V/genetics
MH  - Female
MH  - Follistatin/blood/*metabolism
MH  - Follow-Up Studies
MH  - Forkhead Transcription Factors/genetics/metabolism
MH  - Gene Expression
MH  - Hepatocyte Nuclear Factor 4/genetics/*metabolism
MH  - Hepatocytes/metabolism
MH  - Humans
MH  - Liver Failure, Acute/chemically induced/*metabolism/pathology/surgery
MH  - Liver Regeneration
MH  - Liver Transplantation
MH  - Male
MH  - Metronidazole
MH  - Mice
MH  - Middle Aged
MH  - Prognosis
MH  - Promoter Regions, Genetic
MH  - Prospective Studies
MH  - Prothrombin/genetics
MH  - Signal Transduction
MH  - Smad2 Protein/genetics/metabolism
MH  - Smad3 Protein/genetics/metabolism
MH  - Smad4 Protein/genetics
MH  - Stem Cells/metabolism
MH  - Transforming Growth Factor beta1/genetics
MH  - Zebrafish
EDAT- 2021/08/27 06:00
MHDA- 2022/03/03 06:00
CRDT- 2021/08/26 06:27
PHST- 2021/07/01 00:00 [revised]
PHST- 2021/04/25 00:00 [received]
PHST- 2021/08/15 00:00 [accepted]
PHST- 2021/08/27 06:00 [pubmed]
PHST- 2022/03/03 06:00 [medline]
PHST- 2021/08/26 06:27 [entrez]
AID - 01515467-202202000-00011 [pii]
AID - 10.1002/hep.32119 [doi]
PST - ppublish
SO  - Hepatology. 2022 Feb;75(2):322-337. doi: 10.1002/hep.32119. Epub 2021 Dec 14.