التفاصيل البيبلوغرافية
| العنوان: |
Insulin determines TGF-β effects on HNF4α transcription in hepatocytes |
| المؤلفون: |
Feng, Rilu, Tong, Chenhao, Lin, Tao, Liu, Hui, Shao, Chen, Li, Yujia, Sticht, Carsten, Kan, Kejia, Li, Xiaofeng, Liu, Rui, Wang, Sai, Wang, Shanshan, Munker, Stefan, Niess, Hanno, Meyer, Christoph, Liebe, Roman, Ebert, Matthias P., Dooley, Steven, Wang, Hua, Ding, Huiguo, Weng, Hong-Lei |
| المصدر: |
American Journal of Pathology; 20230101, Issue: Preprints |
| مستخلص: |
Loss of hepatic HNF4α expression is frequently observed in end-stage liver disease (ESLD) and associated with loss of vital liver functions and thus increases mortality. Loss of HNF4α expression is mediated by inflammatory cytokines such as 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 CBP/p300 to the HNF4α promoter. The recruitment of CBP/p300 is indispensable for C/EBPα binding, another essential requirement for constitutive HNF4α expression in hepatocytes. Consistent with the in vitroobservation, 67 out of 98 patients positive for hepatic HNF4α express both p-SMAD2 and C/EBPα, whereas 22 patients negative for HNF4α expression lack either p-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 negative for C/EBPα lack membrane GLUT2 expression in hepatocytes, indicating insulin resistance. Taken together, hepatic insulin sensitivity is essential for hepatic HNF4α expression in the condition of inflammation. |
| قاعدة البيانات: |
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