Choline Kinase Alpha Is a Novel Transcriptional Target of the Brg1 in Hepatocyte: Implication in Liver Regeneration.

Ming Kong,Xiulian Miao,Wenhui Dong,Chengping Li,Qing Ye,Huihui Xu,Yong Xu,Zhiwen Fan,Yutong Wang,Yan Guo

doi:10.3389/fcell.2021.705302

Abstract

Liver regeneration is a key compensatory process in response to liver injury serving to contain damages and to rescue liver functions. Hepatocytes, having temporarily exited the cell cycle after embryogenesis, resume proliferation to regenerate the injured liver parenchyma. In the present study we investigated the transcriptional regulation of choline kinase alpha (Chka) in hepatocytes in the context of liver regeneration. We report that Chka expression was significantly up-regulated in the regenerating livers in the partial hepatectomy (PHx) model and the acetaminophen (APAP) injection model. In addition, treatment with hepatocyte growth factor (HGF), a strong pro-proliferative cue, stimulated Chka expression in primary hepatocytes. Chka depletion attenuated HGF-induced proliferation of hepatocytes as evidenced by quantitative PCR and Western blotting measurements of pro-proliferative genes as well as EdU incorporation into replicating DNA. Of interest, deletion of Brahma-related gene 1 (Brg1), a chromatin remodeling protein, attenuated Chka induction in the regenerating livers in mice and in cultured hepatocytes. Further analysis revealed that Brg1 interacted with hypoxia-inducible factor 1 alpha (HIF-1α) to directly bind to the Chka promoter and activate Chka transcription. Finally, examination of human acute liver failure (ALF) specimens identified a positive correlation between Chka expression and Brg1 expression. In conclusion, our data suggest that Brg1-dependent trans-activation of Chka expression may contribute to liver regeneration.

Highlights

Acute or chronic loss of liver function following a wide range of injuries disrupts internal homeostasis and leads to liver failure with life-threatening consequences (Arroyo et al, 2020)
In the first model in which PHx was performed in C57B6/L mice, it was observed that choline kinase alpha (Chka) expression, as measured by quantitative PCR, started to go up as early as 12 h after the surgery; Chka expression peaked at 24 h and gradually declined until it reached basal levels at 72 h (Figure 1A)
In the second model in which C57B6/L mice were injected with a single dose of acetaminophen to induce acute liver injury, liver regeneration, as judged by the induction of cyclin D1 (Ccnd1) and cyclin A2 (Ccna2), was observed as early as 12 h after the injection (Figure 1D); Chka expression was up-regulated trending closely with the progression of liver regeneration (Figures 1D–F)

Summary

Introduction

Acute or chronic loss of liver function following a wide range of injuries disrupts internal homeostasis and leads to liver failure with life-threatening consequences (Arroyo et al, 2020). Having temporarily exited the cell cycle, hepatocytes could resume proliferation to replenish the loss of liver parenchyma and alleviate the decline of liver function. Proliferation of quiescent hepatocyte and liver regeneration are guided by a complex signaling network. Recombinant HGF appears to confer protection against liver failure by boosting liver regeneration in mice (Kosai et al, 1999) and in humans (Cui et al, 2008). When stimulated by HGF, hepatocytes undergo marked transcriptomic alterations with multiple clusters of genes being up- or down-regulated (KaposiNovak et al, 2006). Regulatory mechanisms underlying these transcription events and the implications in liver regeneration have yet to be fully understood

Methods

Results

Conclusion