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

Estrogen receptors orchestrate cell growth and differentiation to facilitate liver regeneration.

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Graduate Institution of Clinical Medical Science, and Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan 40403.
Department of Trauma and Critical Care, Changhua Christian Hospital, Changhua, Taiwan.
Sex Hormone Research Center, Organ Transplantation Center, and Department of OBs & GYN, China Medical University Hospital, Taichung, Taiwan 40403.
Departments of Urology and Pathology, University of Rochester Medical Center, Rochester, NY 14642, USA.
Department of OBS & GYN, BenQ Medical Center, Nanjing Medical University, Suzhou, Jiangsu Province, China 215004.


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.


estrogen receptor; liver failure; liver regeneration

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