Role of hepatocyte nuclear factor 4α in control of blood coagulation factor gene expression

Hepatocyte nuclear factor-4α (HNF4α) is known as the master regulator of hepatocyte differentiation. Recent studies indicate that HNF4α may inhibit hepatocyte proliferation via mechanisms that have yet to be identified. Using a HNF4α knockdown mouse model based on delivery of inducible Cre recombinase via an adeno-associated virus 8 viral vector, we investigated the role of HNF4α in the regulation of hepatocyte proliferation. Hepatocyte-specific deletion of HNF4α resulted in increased hepatocyte proliferation. Global gene expression analysis showed that a majority of the downregulated genes were previously known HNF4α target genes involved in hepatic differentiation. Interestingly, ≥500 upregulated genes were associated with cell proliferation and cancer. Furthermore, we identified potential negative target genes of HNF4α, many of which are involved in the stimulation of proliferation. Using chromatin immunoprecipitation analysis, we confirmed binding of HNF4α at three of these genes. Furthermore, overexpression of HNF4α in mouse hepatocellular carcinoma cells resulted in a decrease in promitogenic gene expression and cell cycle arrest. Taken together, these data indicate that, apart from its role in hepatocyte differentiation, HNF4α actively inhibits hepatocyte proliferation by repression of specific promitogenic genes.

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RIFAMPICIN INDUCTION OF CYP3A4 REQUIRES PREGNANE X RECEPTOR CROSS TALK WITH HEPATOCYTE NUCLEAR FACTOR 4α AND COACTIVATORS, AND SUPPRESSION OF SMALL HETERODIMER PARTNER GENE EXPRESSION

Drug Metabolism and Disposition ◽

10.1124/dmd.105.007575 ◽

2006 ◽

Vol 34 (5) ◽

pp. 756-764 ◽

Cited By ~ 77

Author(s):

Tiangang Li ◽

John Y. L. Chiang

Keyword(s):

Gene Expression ◽

Cross Talk ◽

Pregnane X Receptor ◽

Nuclear Factor ◽

Hepatocyte Nuclear Factor ◽

Small Heterodimer Partner ◽

Partner Gene ◽

Hepatocyte Nuclear Factor 4Α ◽

Receptor Cross Talk

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

10.1101/304808 ◽

2018 ◽

Author(s):

Ian Huck ◽

Sumedha Gunewardena ◽

Regina Espanol-Suner ◽

Holger Willenbring ◽

Udayan Apte

Keyword(s):

Gene Expression ◽

Liver Regeneration ◽

Target Gene ◽

Nuclear Factor ◽

Hepatocyte Nuclear Factor ◽

Hepatic Differentiation ◽

Target Gene Expression ◽

Protein Levels ◽

Hepatocyte Nuclear Factor 4

AbstractHepatocyte 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 c-myc 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.

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