PMID- 35257388 OWN - NLM STAT- MEDLINE DCOM- 20221115 LR - 20230309 IS - 1527-3350 (Electronic) IS - 0270-9139 (Linking) VI - 76 IP - 6 DP - 2022 Dec TI - A hierarchical regulatory network ensures stable albumin transcription under various pathophysiological conditions. PG - 1673-1689 LID - 10.1002/hep.32414 [doi] AB - BACKGROUND AND AIMS: It remains unknown how patients with liver failure maintain essential albumin levels. Here, we delineate a hierarchical transcription regulatory network that ensures albumin expression under different disease conditions. APPROACH AND RESULTS: We examined albumin levels in liver tissues and serum in 157 patients, including 84 with HCC, 38 decompensated cirrhosis, and 35 acute liver failure. Even in patients with liver failure, the average serum albumin concentrations were 30.55 g/L. In healthy subjects and patients with chronic liver diseases, albumin was expressed in hepatocytes. In patients with massive hepatocyte loss, albumin was expressed in liver progenitor cells (LPCs). The albumin gene (ALB) core promoter possesses a TATA box and nucleosome-free area, which allows constitutive RNA polymerase II binding and transcription initiation. Chromatin immunoprecipitation assays revealed that hepatocyte nuclear factor 4 alpha (HNF4alpha), CCAAT/enhancer-binding protein alpha (C/EBPalpha), and forkhead box A2 (FOXA2) bound to the ALB enhancer. Knockdown of either of these factors reduced albumin expression in hepatocytes. FOXA2 acts as a pioneer factor to support HNF4alpha and C/EBPalpha. In hepatocytes lacking HNF4alpha and C/EBPalpha expression, FOXA2 synergized with retinoic acid receptor (RAR) to maintain albumin transcription. RAR nuclear translocation was induced by retinoic acids released by activated HSCs. In patients with massive hepatocyte loss, LPCs expressed HNF4alpha and FOXA2. RNA sequencing and quantitative PCR analyses revealed that lack of HNF4alpha and C/EBPalpha in hepatocytes increased hedgehog ligand biosynthesis. Hedgehog up-regulates FOXA2 expression through glioblastoma family zinc finger 2 binding to the FOXA2 promoter in both hepatocytes and LPCs. CONCLUSIONS: A hierarchical regulatory network formed by master and pioneer transcription factors ensures essential albumin expression in various pathophysiological conditions. CI - (c) 2022 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases. FAU - Feng, Rilu AU - Feng R AD - Department of Medicine IIMedical Faculty MannheimUniversity Medical Center MannheimHeidelberg UniversityMannheimGermany. FAU - Kan, Kejia AU - Kan K AD - Department of SurgeryMedical Faculty MannheimHeidelberg UniversityMannheimGermany. FAU - Sticht, Carsten AU - Sticht C AD - NGS Core FacilityMedical Faculty MannheimHeidelberg UniversityMannheimGermany. FAU - Li, Yujia AU - Li Y AD - Department of Medicine IIMedical Faculty MannheimUniversity Medical Center MannheimHeidelberg UniversityMannheimGermany. FAU - Wang, Shanshan AU - Wang S AD - Department of Medicine IIMedical Faculty MannheimUniversity Medical Center MannheimHeidelberg UniversityMannheimGermany. AD - Beijing Institute of HepatologyBeijing You'an HospitalCapital Medical UniversityBeijingChina. 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 - Munker, Stefan AU - Munker S AD - Department of Medicine IIUniversity HospitalLudwig-Maximilians-University MunichMunichGermany. AD - Liver Centre MunichUniversity HospitalLudwig-Maximilians-UniversityMunichGermany. FAU - Niess, Hanno AU - Niess H AD - Department of General, Visceral, and Transplant SurgeryLudwig-Maximilians-University MunichMunichGermany. AD - Biobank of the Department of GeneralVisceral and Transplant SurgeryLudwig-Maximilians-UniversityMunichGermany. FAU - Wang, Sai AU - Wang S AD - Department of Medicine IIMedical Faculty MannheimUniversity Medical Center MannheimHeidelberg UniversityMannheimGermany. FAU - Meyer, Christoph AU - Meyer C AD - Department of Medicine IIMedical Faculty MannheimUniversity Medical Center MannheimHeidelberg UniversityMannheimGermany. 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 - Ebert, Matthias P AU - Ebert MP AD - Department of Medicine IIMedical Faculty MannheimUniversity Medical Center MannheimHeidelberg UniversityMannheimGermany. AD - Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty MannheimHeidelberg UniversityMannheimGermany. AD - Clinical Cooperation Unit Healthy MetabolismCenter of Preventive Medicine and Digital HealthMedical Faculty MannheimHeidelberg UniversityMannheimGermany. FAU - Dooley, Steven AU - Dooley S AD - Department of Medicine IIMedical Faculty MannheimUniversity Medical Center MannheimHeidelberg UniversityMannheimGermany. FAU - Ding, Huiguo AU - Ding H AD - Department of Gastroenterology and HepatologyBeijing You'an HospitalAffiliated with Capital Medical UniversityBeijingChina. FAU - Weng, Honglei AU - Weng H AD - Department of Medicine IIMedical Faculty MannheimUniversity Medical Center MannheimHeidelberg UniversityMannheimGermany. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220307 PL - United States TA - Hepatology JT - Hepatology (Baltimore, Md.) JID - 8302946 RN - 0 (Hepatocyte Nuclear Factor 4) RN - 0 (CCAAT-Enhancer-Binding Protein-alpha) RN - 0 (Albumins) SB - IM MH - Humans MH - Animals MH - *Carcinoma, Hepatocellular/genetics/metabolism MH - Hedgehogs/metabolism MH - *Liver Neoplasms/metabolism MH - Hepatocyte Nuclear Factor 4/genetics/metabolism MH - Hepatocytes/metabolism MH - Liver/metabolism MH - CCAAT-Enhancer-Binding Protein-alpha/metabolism MH - Albumins MH - *Liver Failure/metabolism EDAT- 2022/03/09 06:00 MHDA- 2022/11/16 06:00 CRDT- 2022/03/08 05:41 PHST- 2022/01/04 00:00 [revised] PHST- 2021/08/10 00:00 [received] PHST- 2022/02/14 00:00 [accepted] PHST- 2022/03/09 06:00 [pubmed] PHST- 2022/11/16 06:00 [medline] PHST- 2022/03/08 05:41 [entrez] AID - 01515467-202212000-00012 [pii] AID - 10.1002/hep.32414 [doi] PST - ppublish SO - Hepatology. 2022 Dec;76(6):1673-1689. doi: 10.1002/hep.32414. Epub 2022 Mar 7.