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Hepatocyte nuclear factor 4 response to injury involves a rapid decrease in DNA binding and transactivation via a
Xuemei Li1, John Salisbury-Rowswell, Alan D Murdock
1Boston Medical Center, Department of Surgery, Boston, MA 02118, USA.
Abstract:
The injury response is a complex set of events, which represents the reaction of a biological system to a perceived change in its environment in an attempt to maintain system integrity. Isolation of individual events or components of this response cannot describe the overall process, but may reflect general mechanisms that have evolved over time to solve the complex requirements of the injury response. The process, generally termed the acute phase response, is a series of organ-specific responses that begin shortly after a systemic injury. In the liver, this response involves both dramatic inductions and reductions in specific sets of genes, and an overall widespread global change in proteins produced. This can be thought of as a phenotypic change or 'reprogramming' of the liver. These changes in protein production are modulated and regulated at the level of transcription and involve significant manipulations of transcriptional regulatory mechanisms. Hepatocyte nuclear factor 4 (HNF-4) is a liver enriched transcription factor that regulates a large number of liver-specific genes, which play important roles in the critical pathways modulated by the response to injury. HNF-4 also performs an essential role in overall development and is critical for the normal expression of multiple genes in the developed liver, as well as being upstream of HNF-1 in a transcriptional hierarchy that drives hepatocyte differentiation. The role of HNF-4 in regulating liver-specific transcriptional changes directed by injury remains to be defined. In our cell-culture and whole-animal models, we demonstrate that the binding activity of HNF-4 decreases quickly after injury due to post-translational modification by phosphorylation. The mechanisms by which HNF-4 is modified after injury involve the activation of Janus kinase 2 (JAK2) signal transduction pathways, but the direct or indirect interaction of JAK2 with HNF-4 remains to be defined.
Insights
The liver
Area of Science:
- Molecular Biology
- Cellular Biology
- Biochemistry
Background:
- The liver undergoes significant changes during the acute phase response to injury.
- Hepatocyte nuclear factor 4 (HNF-4) is crucial for liver-specific gene expression and development.
- The precise role of HNF-4 in injury-induced liver reprogramming is not fully understood.
Purpose of the Study:
- To investigate the role of Hepatocyte nuclear factor 4 (HNF-4) in the liver's response to injury.
- To elucidate the regulatory mechanisms controlling HNF-4 activity during the acute phase response.
Main Methods:
- Utilized cell-culture and whole-animal models to study liver injury response.
- Investigated post-translational modifications of HNF-4, specifically phosphorylation.
- Examined the involvement of Janus kinase 2 (JAK2) signaling pathways.
Main Results:
- HNF-4 binding activity significantly decreases following systemic injury.
- This reduction in HNF-4 activity is mediated by post-translational modification via phosphorylation.
- Janus kinase 2 (JAK2) signaling pathways are activated and implicated in HNF-4 modification.
Conclusions:
- HNF-4 activity is rapidly downregulated after liver injury through phosphorylation.
- JAK2 signaling is involved in the post-translational modification of HNF-4 during the injury response.
- Further research is needed to define the direct interaction between JAK2 and HNF-4.