Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2023.01.12.523351v1?rss=1

Authors: Feng, R., Tong, C., Lin, T., Liu, H., Shao, C., Li, Y., Sticht, C., Kan, K., Li, X., Liu, R., Wang, S., Wang, S., Munker, S., Niess, H., Meyer, C., Liebe, R., Ebert, M. P., Dooley, S., Wang, H., Ding, H., Weng, H.-L.

Abstract:
To date, epithelial-to-mesenchymal transition (EMT) has been observed in cultured hepatocytes, but not in vivo. TGF-beta is supposed to initiate EMT in hepatocytes by inhibiting the hepatic master transcription factor HNF4alpha through the SMAD2/3 complex. However, we observe that the SMAD2/3 complex is required for HNF4alpha transcription. Besides SMAD2/3, C/EBPalpha is also essential for constitutive HNF4alpha expression in hepatocytes. In contrast to upregulating HNF4alpha transcription, SMAD2/3 represses C/EBPalpha transcription. Therefore, long-term TGF-beta incubation results in C/EBPalpha depletion, which inhibits HNF4alpha expression. Impressively, SMAD2/3 binding to the CEBPA promoter is inhibited by insulin. Maintaining a high insulin concentration in culture medium completely inhibits TGF-beta-induced hepatocyte EMT. Insulin inhibits TGF-beta-induced SMAD2/3 binding to the promoters of core EMT transcription factors e.g., SNAI1. SNAI1 transcription requires both SMAD2/3 and FOXO1 in nuclei. Insulin inhibits SNAI1 transcription through impeding SMAD2/3 binding to its promoter and inducing FOXO1 phosphorylation. Hence, insulin is the key factor that prevents TGF-beta-induced EMT in hepatocytes.

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