Abstract (Expand)
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.
Authors: 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, Hong-Lei Weng
Date Published: 1st Oct 2023
Publication Type: Journal
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