Hepatocyte Nuclear Factor 4 alpha (HNF4α) Activation is Essential for Termination of Liver Regeneration

Abstract

Hepatocyte Nuclear Factor 4 alpha (HNF4α) is critical for hepatic differentiation. Recent studies have highlighted its role in inhibition of hepatocyte proliferation and tumor suppression.However, the role of HNF4α in liver regeneration is not known. We hypothesized that hepatocytes modulate HNF4α activity when navigating between differentiated and proliferative states during liver regeneration. Western blot analysis revealed a rapid decline in nuclear and cytoplasmic HNF4α protein levels accompanied with decreased target gene expression within 1 hour after 2/3 partial hepatectomy (post-PH) in C57BL/6J mice. HNF4α protein expression did not recover to the pre-PH levels until day 3. Hepatocyte-specific deletion of HNF4α (HNF4α-KO) in mice resulted in 100% mortality post-PH despite increased proliferative marker expression throughout regeneration. Sustained loss of HNF4α target gene expression throughout regeneration indicated HNF4α-KO mice were unable to compensate for loss of HNF4α transcriptional activity. Deletion of HNF4α resulted in sustained proliferation accompanied by cmyc and cyclin D1 over expression and a complete deficiency of hepatocyte function after PH. Interestingly, overexpression of degradation-resistant HNF4α in hepatocytes did not prevent initiation of regeneration after PH. Finally, AAV8-mediated reexpression of HNF4α in hepatocytes of HNF4α-KO mice post-PH restored HNF4α protein levels, induced target gene expression and improved survival of HNF4α-KO mice post-PH. In conclusion, these data indicate that HNF4α reexpression following initial decrease is critical for hepatocytes to exit from cell cycle and resume function during the termination phase of liver regeneration. These results reveal the role of HNF4α in liver regeneration and have implications for therapy of liver failure.

Cellular plasticity balances the metabolic and proliferation dynamics of a regenerating liver

“…Consistent with our regulon activity scores, HNF4A protein levels diminish rapidly after PHx, and this initial decrease followed by re-expression is needed for hepatocytes to timely enter and exit the cell cycle and to re-establish mature liver functions once regeneration is complete (Huck et al, 2019).…”

“…The function of hepatocyte nuclear factor 4A (HNF4A), a nuclear receptor, in hepatocyte differentiation is well established (Kyrmizi et al, 2006;Parviz et al, 2003) -as it directs the expression of gene programs involved in xenobiotic, carbohydrate, and fatty acid metabolism as well as in bile acid synthesis, blood coagulation, and ureagenesis (Hayhurst et al, 2001;Inoue et al, 2002b;2006a;2004;2006b;Nishikawa et al, 2015;Schrem et al, 2002). Previous studies have described HNF4A's anti-proliferative effects in hepatocytes (Bonzo et al, 2012;Hatziapostolou et al, 2011;Walesky et al, 2013), and more recently, it was found that HNF4A is indispensable for terminating regeneration after PHx (Huck et al, 2019).…”

Regulation of Liver Regeneration by hepatocyte O-GlcNAcylation in mice

“…Hepatocyte HNF4α deficiency has been linked to spontaneous hepatocyte proliferation as well as defective termination of LR (15,16). Therefore, we investigated HNF4α expression and activity in OGT-KO mice 28 days after PHX.…”

P53/miR-34a/SIRT1 Positive Feedback Loop regulates cell proliferation and promotes cell apoptosis in the termination stage of liver regeneration.

“…A recent study reported that PP2Acα terminates LR in mice via the AKT/GSK3β/Cyclin D1 signaling pathway [6]. Ian Huck found that knockout of hepatocyte nuclear factor 4 alpha increased hepatocyte proliferation throughout LR and that HNF4a activation was crucial for the termination of liver regeneration in mice [7].…”