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Insulin determines transforming growth factor β effects on hepatocyte nuclear factor 4α transcription in hepatocytes

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 increasing mortality. Loss of HNF4α expression is mediated by inflammatory cytokines, such as transforming growth factor (TGF)-β. However,...

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Hauptverfasser: Feng, Rilu (VerfasserIn) , Tong, Chenhao (VerfasserIn) , Lin, Tao (VerfasserIn) , Liu, Hui (VerfasserIn) , Shao, Chen (VerfasserIn) , Li, Yujia (VerfasserIn) , Sticht, Carsten (VerfasserIn) , Kan, Kejia (VerfasserIn) , Li, Xiaofeng (VerfasserIn) , Liu, Rui (VerfasserIn) , Wang, Sai (VerfasserIn) , Wang, Shanshan (VerfasserIn) , Munker, Stefan (VerfasserIn) , Nieß, Hanno (VerfasserIn) , Meyer, Christoph (VerfasserIn) , Liebe, Roman (VerfasserIn) , Ebert, Matthias (VerfasserIn) , Dooley, Steven (VerfasserIn) , Wang, Hua (VerfasserIn) , Ding, Huiguo (VerfasserIn) , Weng, Honglei (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: January 2024
In: The American journal of pathology
Year: 2024, Jahrgang: 194, Heft: 1, Pages: 52-70
ISSN:1525-2191
DOI:10.1016/j.ajpath.2023.09.009
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.ajpath.2023.09.009
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S0002944023003656
Volltext
Verfasserangaben:Rilu Feng, Chenhao Tong, Tao Lin, Hui Liu, Chen Shao, Yujia Li, Carsten Sticht, Kejia Kan, Xiaofeng Li, Rui Liu, Sai Wang, Shanshan Wang, Stefan Munker, Hanno Niess, Christoph Meyer, Roman Liebe, Matthias P. Ebert, Steven Dooley, Hua Wang, Huiguo Ding, and Hong-Lei Weng
Beschreibung
Zusammenfassung: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 increasing 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. Herein, TGF-β did not directly inhibit HNF4α but contributed 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 expressed both phospho-SMAD2 and C/EBPα, whereas 22 patients without HNF4α expression lacked either phospho-SMAD2 or C/EBPα. In contrast to the observed induction of HNF4α, SMAD2/3 inhibited C/EBPα transcription. Long-term TGF-β incubation resulted in C/EBPα depletion, which abrogated HNF4α expression. Intriguingly, SMAD2/3 inhibitory binding to the C/EBPα promoter was abolished by insulin. Two-thirds of patients without C/EBPα lacked membrane glucose transporter type 2 expression in hepatocytes, indicating insulin resistance. Taken together, these data indicate that hepatic insulin sensitivity is essential for hepatic HNF4α expression in the condition of inflammation.
Beschreibung:Online verfügbar: 10. Oktober 2023, Artikelversion: 18. Dezember 2023
Gesehen am 03.04.2024
Beschreibung:Online Resource
ISSN:1525-2191
DOI:10.1016/j.ajpath.2023.09.009

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