Tao Lin1, Shanshan Wang1,2, Stefan Munker3, Kyounghwa Jung4, Ricardo U Macías-Rodríguez5, Astrid Ruiz-Margáin5, Robert Schierwagen6, Hui Liu7, Chen Shao7, Chunlei Fan8, Rilu Feng1, Xiaodong Yuan1, Sai Wang1, Franziska Wandrer9, Christoph Meyer1, Ralf Wimmer3, Roman Liebe10,11, Jens Kroll12, Long Zhang13, Tobias Schiergens14, Peter Ten Dijke15, Andreas Teufel16,17, Alexander Marx18, Peter R Mertens19, Hua Wang20,21, Matthias P A Ebert22,23,24, Heike Bantel9, Enrico N De Toni3, Jonel Trebicka6,25, Steven Dooley1, Donghun Shin4, Huiguo Ding8, Hong-Lei Weng1. 1. Department of Medicine II, Section Molecular Hepatology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. 2. Beijing Institute of Hepatology, Beijing You'an Hospital, Capital Medical University, Beijing, China. 3. Department of Medicine II, University Hospital, Campus Großhadern, LMU Munich, Munich, Germany. 4. Department of Developmental Biology, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. 5. Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico city, Mexico. 6. Translational Hepatology, Medical Department I, Frankfurt University Hospital, Frankfurt, Germany. 7. Department of Pathology, Beijing You'an Hospital, Affiliated with Capital Medical University, Beijing, China. 8. Department of Gastroenterology and Hepatology, Beijing You'an Hospital, Affiliated with Capital Medical University, Beijing, China. 9. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. 10. Clinic of Gastroenterology, Hepatology and Infectious Diseases, Heinrich Heine University, Düsseldorf, Germany. 11. Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany. 12. Vascular Biology and Tumor Angiogenesis, European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. 13. Life Sciences Institute and Innovation Center for Cell Signaling Network, Hangzhou, China. 14. Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, University Hospital, LMU Munich, Munich, Germany. 15. Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands. 16. Division of Hepatology, Division of Clinical Bioinformatics, Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. 17. Clinical Cooperation Unit Healthy Metabolism, Center for Preventive Medicine and Digital Health Baden-Württemberg, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. 18. Institute of Pathology, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany. 19. Clinic of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke-University, Magdeburg, Germany. 20. Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, China. 21. Inflammation and Immune Mediated Disease Laboratory of Anhui Province, Hefei, China. 22. Mannheim Institute for Innate Immunoscience, Mannheim, Germany. 23. Clinical Cooperation Unit Healthy Metabolism, Center of Preventive Medicine and Digital Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. 24. Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. 25. European Foundation for Study of Chronic Liver Failure, Barcelona, Spain.
Abstract
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 4α (HNF4α), 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, HNF4α, 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 HNF4α in either LPCs or remaining hepatocytes. As in hepatocytes, HNF4α controls the expression of coagulation factors by binding to their promoters in LPC. HNF4α 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-β 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 HNF4α 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-HNF4α-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.
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 4α (HNF4α), 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, HNF4α, 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 HNF4α in either LPCs or remaining hepatocytes. As in hepatocytes, HNF4α controls the expression of coagulation factors by binding to their promoters in LPC. HNF4α 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-β 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 HNF4α 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-HNF4α-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.