An Integrated Approach for the Identification of HNF4α-Centered Transcriptional Regulatory Networks During Early Liver Regeneration

Jiao, Heng; Zhu, Yanhua; Lu, Shan; Zheng, Yan; Chen, Huan

doi:10.1159/000430195

Cited by 10 publications

(13 citation statements)

References 29 publications

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“…We also observed decreased HNF4α activity as measured by its target gene expression . Our observations independently reproduce a microarray study describing decreased HNF4α target gene expression 4 hours post‐PH . This highlights functional differences between quiescent and proliferating hepatocytes and suggests that restoring HNF4α in hepatocytes responding to chronic injury could successfully restore hepatic function .…”

Section: Discussionsupporting

confidence: 83%

“…(12) Our observations independently reproduce a microarray study describing decreased HNF4α target gene expression 4 hours post-PH. (43) This highlights functional differences between quiescent and proliferating hepatocytes and suggests that restoring HNF4α in hepatocytes responding to chronic injury could successfully restore hepatic function. (9,44) These studies are consistent with a previous observation of decreased periportal HNF4α staining after PH.…”

Section: Discussionmentioning

confidence: 94%

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

et al. 2019

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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 (LR) is not known. We hypothesized that hepatocytes modulate HNF4α activity when navigating between differentiated and proliferative states during LR. Western blotting analysis revealed a rapid decline in nuclear and cytoplasmic HNF4α protein levels, accompanied with decreased target gene expression, within 1 hour after two‐thirds partial hepatectomy (post‐PH) in C57BL/6J mice. HNF4α protein expression did not recover to pre‐PH levels until day 3. Hepatocyte‐specific deletion of HNF4α (HNF4α‐KO [knockout]) 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 that 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 overexpression and a complete deficiency of hepatocyte function after PH. Interestingly, overexpression of degradation‐resistant HNF4α in hepatocytes delayed, but did not prevent, initiation of regeneration after PH. Finally, adeno‐associated virus serotype 8 (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. Conclusion: 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 LR. These results indicate the role of HNF4α in LR and have implications for therapy of liver failure.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 94%

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

et al. 2019

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“…Decrease in expression of HNF4α protein after PH resulted in decrease in its transcriptional activity as measured by its target genes, which play a critical role in liver physiology (14). Our observations independently reproduce a microarray study describing decreased HNF4α target gene expression 4 hours post-PH (42). This highlights functional differences between quiescent and proliferating hepatocytes and suggests restoring HNF4α in hepatocytes responding to chronic injury could successfully restore hepatic function (9,43).…”

Section: Discussionsupporting

confidence: 80%

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

Huck

Gunewardena

Español–Suñer

et al. 2018

Preprint

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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.

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“…Many important genes, such as interleukin-6, c-fos, c-jun, and hepatocyte nuclear factor 4a (HNF-4a), play a vital role in driving hepatocyte entry into cell cycle at the initiation step (Riehle et al, 2011;Jiao et al, 2015). We measured the mRNA levels of these transcripts and found that WZ had no effect on Hnf-4a expression but significantly up-regulated c-jun and c-fos at day1 and day 2, respectively, in PHX/ WZ-treated mice.…”

Section: Discussionmentioning

confidence: 99%

Schisandra sphenanthera Extract Facilitates Liver Regeneration after Partial Hepatectomy in Mice

Fan

et al. 2016

Drug Metabolism and Disposition

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Liver regeneration after surgical liver resection is crucial for the restoration of liver mass and the recovery of liver function. Schisandra sphenanthera extract (Wuzhi tablet, WZ) is a preparation of an extract from the dried ripe fruit of Schisandra sphenanthera Rehd. et Wils, a traditional hepatoprotective herb. Previously, we found that WZ could induce liver regeneration-related genes against acetaminopheninduced liver injury. However, whether WZ can directly facilitate liver regeneration after liver resection remains unknown. We investigated whether WZ has potential in promoting liver regeneration after a partial hepatectomy (PHX) in mice. Remnant livers were collected 1, 1.5, 2, 3, 5, 7, and 10 days after PHX. Hepatocyte proliferation was assessed using the Ki-67 labeling index. Western blot analysis was performed on proteins known to be involved in liver regeneration. The results demonstrated that WZ significantly increased the liver-to-body weight ratio of mice after PHX but had no effect on that of mice after a sham operation. Additionally, the peak hepatocyte proliferation was observed at 1.5 days in PHX/WZ-treated mice but at 2 days in PHX/saline-treated mice, as evidenced by the Ki-67 positive ratio. Furthermore, WZ significantly increased the protein expression of ligand-induced phosphorylation of epidermal growth factor receptor and up-regulated cyclin D1, cyclin D-dependent kinase 4, phosphorylated retinoblastoma, and proliferating cell nuclear antigen protein expression and down-regulated the expression of cell cycle inhibitors p21 and p27 in the regenerative process after PHX. These results demonstrate that WZ significantly facilitates hepatocyte proliferation and liver regeneration after PHX.

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An Integrated Approach for the Identification of HNF4α-Centered Transcriptional Regulatory Networks During Early Liver Regeneration

Cited by 10 publications

References 29 publications

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

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

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

Schisandra sphenanthera Extract Facilitates Liver Regeneration after Partial Hepatectomy in Mice

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