Insulin Determines Transforming Growth Factor β Effects on Hepatocyte Nuclear Factor 4α Transcription in Hepatocytes.

Journal

The American journal of pathology
ISSN: 1525-2191
Titre abrégé: Am J Pathol
Pays: United States
ID NLM: 0370502

Informations de publication

Date de publication:
10 Oct 2023
Historique:
received: 16 05 2023
revised: 19 08 2023
accepted: 12 09 2023
pubmed: 12 10 2023
medline: 12 10 2023
entrez: 11 10 2023
Statut: aheadofprint

Résumé

Loss of hepatocyte nuclear factor 4α (HNF4α) expression is frequently observed in end-stage liver disease and associated with loss of vital liver functions, thus increasjng mortality. Loss of HNF4α expression is mediated by inflammatory cytokines, such as transforming growth factor (TGF)-β. However, details of how HNF4α is suppressed are largely unknown to date. This study reports that TGF-β does not directly inhibit HNF4α but contributes to its transcriptional regulation by SMAD2/3 recruiting acetyltransferase CREB-binding protein/p300 to the HNF4α promoter. The recruitment of CREB-binding protein/p300 is indispensable for CCAAT/enhancer-binding protein α (C/EBPα) binding, another essential requirement for constitutive HNF4α expression in hepatocytes. Consistent with the in vitro observation, 67 of 98 patients with hepatic HNF4α express both phospho-SMAD2 and C/EBPα, whereas 22 patients without HNF4α expression lack either phospho-SMAD2 or C/EBPα. In contrast to the observed induction of HNF4α, SMAD2/3 inhibits C/EBPα transcription. Therefore, long-term TGF-β incubation results in C/EBPα depletion, which abrogates HNF4α expression. Intriguingly, SMAD2/3 inhibitory binding to the C/EBPα promoter is abolished by insulin. Two-thirds of patients without C/EBPα lack membrane glucose transporter type 2 expression in hepatocytes, indicating insulin resistance. Taken together, hepatic insulin sensitivity is essential for hepatic HNF4α expression in the condition of inflammation.

Identifiants

DOI: 10.1016/j.ajpath.2023.09.009 PMID: 37820926
pubmed: 37820926
pii: S0002-9440(23)00365-6
doi: 10.1016/j.ajpath.2023.09.009
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2023 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Disclosure Statement None declared.

Auteurs

Rilu Feng (R)

Medical Faculty Mannheim, Section Molecular Hepatology, Department of Medicine II, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany.

Chenhao Tong (C)

Medical Faculty Mannheim, Section Molecular Hepatology, Department of Medicine II, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany.

Tao Lin (T)

Medical Faculty Mannheim, Section Molecular Hepatology, Department of Medicine II, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany.

Hui Liu (H)

Department of Pathology, Beijing You'an Hospital, Affiliated with Capital Medical University, Beijing, China.

Chen Shao (C)

Department of Pathology, Beijing You'an Hospital, Affiliated with Capital Medical University, Beijing, China.

Yujia Li (Y)

Medical Faculty Mannheim, Section Molecular Hepatology, Department of Medicine II, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany.

Carsten Sticht (C)

NGS Core Facility, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Kejia Kan (K)

Medical Faculty Mannheim, Department of Surgery, Heidelberg University, Mannheim, Germany.

Xiaofeng Li (X)

Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.

Rui Liu (R)

Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.

Sai Wang (S)

Medical Faculty Mannheim, Section Molecular Hepatology, Department of Medicine II, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany.

Shanshan Wang (S)

Beijing Institute of Hepatology, Beijing You'an Hospital, Capital Medical University, Beijing, China.

Stefan Munker (S)

Department of Medicine II, Liver Centre Munich, University Hospital, LMU Munich, Campus Großhadern, Munich, Germany; Liver Centre Munich, University Hospital, Ludwig-Maximilians-University, Munich, Germany.

Hanno Niess (H)

Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany; Biobank of the Department of General, Visceral and Transplant Surgery, Ludwig-Maximilians-University, Munich, Germany.

Christoph Meyer (C)

Medical Faculty Mannheim, Section Molecular Hepatology, Department of Medicine II, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany.

Roman Liebe (R)

Clinic of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke-Unitersity, Magdeburg, Germany.

Matthias P Ebert (MP)

Medical Faculty Mannheim, Department of Medicine II, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany; Medical Faculty Mannheim, Mannheim Institute for Innate Immunoscience (MI3), Heidelberg University, Mannheim, Germany; Medical Faculty Mannheim, Clinical Cooperation Unit Healthy Metabolism, Center of Preventive Medicine and Digital Health, Heidelberg University, Mannheim, Germany.

Steven Dooley (S)

Medical Faculty Mannheim, Section Molecular Hepatology, Department of Medicine II, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany.

Hua Wang (H)

Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.

Huiguo Ding (H)

Department of Gastroenterology and Hepatology, Beijing You'an Hospital, Affiliated with Capital Medical University, Beijing, China.

Hong-Lei Weng (HL)

Medical Faculty Mannheim, Section Molecular Hepatology, Department of Medicine II, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany. Electronic address: honglei.weng@medma.uni-heidelberg.de.

Classifications MeSH