Insulin Determines Transforming Growth Factor b Effects on Hepatocyte Nuclear Factor 4a Transcription in Hepatocytes

Loss of hepatocyte nuclear factor 4a (HNF4a) expression is frequently observed in end-stage liver disease and associated with loss of vital liver functions, thus increasing mortality. Loss of HNF4a expression is mediated by inflammatory cytokines, such as transforming growth factor (TGF)-0. However, details of how HNF4a is suppressed are largely unknown to date. Herein, TGF-0 did not directly inhibit HNF4a but contributed to its transcriptional regulation by SMAD2/3 recruiting acetyltransferase CREB-binding protein/p300 to the HNF4a promoter. The recruitment of CREB-binding protein/p300 is indispensable for CCAAT/enhancer-binding protein a (C/EBPa) binding, another essential requirement for constitutive HNF4a expression in hepatocytes. Consistent with the in vitro observation, 67 of 98 patients with hepatic HNF4a expressed both phospho-SMAD2 and C/EBPa, whereas 22 patients without HNF4a expression lacked either phospho-SMAD2 or C/EBPa. In contrast to the observed induction of HNF4a, SMAD2/3 inhibited C/EBPa transcription. Longterm TGF-0 incubation resulted in C/EBPa depletion, which abrogated HNF4a expression. Intriguingly, SMAD2/3 inhibitory binding to the C/EBPa promoter was abolished by insulin. Two-thirds of patients without C/EBPa 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 HNF4a expression in the condition of inflammation. (Am J Pathol 2024, 194: 52e70; https://doi.org/10.1016/ j.ajpath.2023.09.009)