Estrogen receptors orchestrate cell growth and differentiation to facilitate liver regeneration

Theranostics. 2018 Apr 9;8(10):2672-2682. doi: 10.7150/thno.23624. eCollection 2018.


Background and Aims: Improving liver regeneration (LR) capacity and thereby liver function reserve is a critical bridging strategy for managing liver failure patients. Since estrogen signaling may participate in LR, our aim was to characterize the roles of ERα and ERβ in LR. Methods: LR capacity and estradiol levels following 2/3rd partial hepatectomy (PHx) were compared in ERα-KO or ERβ-KO vs. wildtype mice. The ERα- or ERβ-related transcriptome and interactome were analyzed from regenerating livers, and then bioinformatics was used for pathway discovery and analysis of interactome-transcriptome relationships. Human hepatic progenitors (HepRG cells) and mouse Hepa1-6 hepatocytes were used to elucidate molecular interactions and functions. Results: This paper demonstrated that estrogen signals orchestrate hepatic repopulation and differentiation via distinct transcriptome patterns governed by ERα or ERβ. Cell repopulation pathway was associated with the ERα-transcriptome, but cell differentiation and metabolic function were associated with the ERβ transcriptome. Mechanistic studies linking ERs interactomes and transcriptomes discovered that ERα-Chd1 interaction promoted cell growth by upregulating Ssxb6, Crygc, and Cst1; and, ERβ-Ube3a interaction facilitated hepatic progenitor cell differentiation to hepatocytes and cholangiocytes, specifically by upregulating Ifna5. Conclusions: ERα and ERβ orchestrate liver cell proliferation and differentiation respectively, thereby promoting LR.

Keywords: estrogen receptor; liver failure; liver regeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation*
  • Cell Line, Tumor
  • Female
  • HEK293 Cells
  • Hepatocytes / cytology
  • Hepatocytes / metabolism
  • Humans
  • Liver / cytology
  • Liver / metabolism*
  • Liver / physiology
  • Liver Regeneration*
  • Male
  • Mice
  • Receptors, Estrogen / metabolism*
  • Stem Cells / cytology
  • Stem Cells / metabolism
  • Transcriptome


  • Receptors, Estrogen