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J Hepatol. 2016 Feb;64(2):316-325. doi: 10.1016/j.jhep.2015.10.017. Epub 2015 Oct 24.

Bromodomain and extraterminal (BET) proteins regulate biliary-driven liver regeneration.

Author information

1
Department of Developmental Biology, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA.
2
Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15260, USA.
3
Department of Developmental Biology, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA. Electronic address: donghuns@pitt.edu.

Abstract

BACKGROUND & AIMS:

During liver regeneration, hepatocytes are derived from pre-existing hepatocytes. However, if hepatocyte proliferation is compromised, biliary epithelial cells (BECs) become the source of new hepatocytes. We recently reported on a zebrafish liver regeneration model in which BECs extensively contribute to hepatocytes. Using this model, we performed a targeted chemical screen to identify important factors that regulate BEC-driven liver regeneration, the mechanisms of which remain largely unknown.

METHODS:

Using Tg(fabp10a:CFP-NTR) zebrafish, we examined the effects of 44 selected compounds on BEC-driven liver regeneration. Liver size was assessed by fabp10a:DsRed expression; liver marker expression was analyzed by immunostaining, in situ hybridization and quantitative PCR. Proliferation and apoptosis were also examined. Moreover, we used a mouse liver injury model, choline-deficient, ethionine-supplemented (CDE) diet.

RESULTS:

We identified 10 compounds that affected regenerating liver size. Among them, only bromodomain and extraterminal domain (BET) inhibitors, JQ1 and iBET151, blocked both Prox1 and Hnf4a induction in BECs. BET inhibition during hepatocyte ablation blocked BEC dedifferentiation into hepatoblast-like cells (HB-LCs). Intriguingly, after JQ1 washout, liver regeneration resumed, indicating temporal, but not permanent, perturbation of liver regeneration by BET inhibition. BET inhibition after hepatocyte ablation suppressed the proliferation of newly generated hepatocytes and delayed hepatocyte maturation. Importantly, Myca overexpression, in part, rescued the proliferation defect. Furthermore, oval cell numbers in mice fed CDE diet were greatly reduced upon JQ1 administration, supporting the zebrafish findings.

CONCLUSIONS:

BET proteins regulate BEC-driven liver regeneration at multiple steps: BEC dedifferentiation, HB-LC proliferation, the proliferation of newly generated hepatocytes, and hepatocyte maturation.

KEYWORDS:

BET inhibitors; Dedifferentiation; JQ1; Liver progenitor cells; Liver regeneration; Oval cells; Zebrafish

PMID:
26505118
PMCID:
PMC4718879
DOI:
10.1016/j.jhep.2015.10.017
[Indexed for MEDLINE]
Free PMC Article

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