Hepatocyte Nuclear Factor 4 Alpha Activation Is Essential for Termination of Liver Regeneration in Mice.

ABSTRACT: Hepatocyte nuclear factor 4 alpha (HNF4?) is critical for hepatic differentiation. Recent studies have highlighted its role in inhibition of hepatocyte proliferation and tumor suppression. However, the role of HNF4? in liver regeneration (LR) is not known. We hypothesized that hepatocytes modulate HNF4? activity when navigating between differentiated and proliferative states during LR. Western blotting analysis revealed a rapid decline in nuclear and cytoplasmic HNF4? protein levels, accompanied with decreased target gene expression, within 1 hour after two-thirds partial hepatectomy (post-PH) in C57BL/6J mice. HNF4? protein expression did not recover to pre-PH levels until day 3. Hepatocyte-specific deletion of HNF4? (HNF4?-KO [knockout]) in mice resulted in 100% mortality post-PH, despite increased proliferative marker expression throughout regeneration. Sustained loss of HNF4? target gene expression throughout regeneration indicated that HNF4?-KO mice were unable to compensate for loss of HNF4? transcriptional activity. Deletion of HNF4? resulted in sustained proliferation accompanied by c-Myc and cyclin D1 overexpression and a complete deficiency of hepatocyte function after PH. Interestingly, overexpression of degradation-resistant HNF4? in hepatocytes delayed, but did not prevent, initiation of regeneration after PH. Finally, adeno-associated virus serotype 8 (AAV8)-mediated reexpression of HNF4? in hepatocytes of HNF4?-KO mice post-PH restored HNF4? protein levels, induced target gene expression, and improved survival of HNF4?-KO mice post-PH. Conclusion: In conclusion, these data indicate that HNF4? reexpression following initial decrease is critical for hepatocytes to exit from cell cycle and resume function during the termination phase of LR. These results indicate the role of HNF4? in LR and have implications for therapy of liver failure.

SUBMITTER: Huck I 

PROVIDER: S-EPMC6551324 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature