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

ABSTRACT: 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 ER? and ER? in LR. Methods: LR capacity and estradiol levels following 2/3rd partial hepatectomy (PHx) were compared in ER?-KO or ER?-KO vs. wildtype mice. The ER?- or ER?-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 ER? or ER?. Cell repopulation pathway was associated with the ER?-transcriptome, but cell differentiation and metabolic function were associated with the ER? transcriptome. Mechanistic studies linking ERs interactomes and transcriptomes discovered that ER?-Chd1 interaction promoted cell growth by upregulating Ssxb6, Crygc, and Cst1; and, ER?-Ube3a interaction facilitated hepatic progenitor cell differentiation to hepatocytes and cholangiocytes, specifically by upregulating Ifna5. Conclusions: ER? and ER? orchestrate liver cell proliferation and differentiation respectively, thereby promoting LR.

SUBMITTER: Kao TL

PROVIDER: S-EPMC5957001 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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

Kao Ta-Lun TL Kuan Yu-Ping YP Cheng Wei-Chung WC Chang Wei-Chun WC Jeng Long-Bin LB Yeh Shuyuan S Ma Wen-Lung WL

Theranostics 20180409 10

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 ana ...[more]

PMID: 29774067

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Project description:Autophagy, or cellular self-digestion, is an essential cellular process imperative for energy homeostasis, development, differentiation, and survival. However, the intrinsic factors that bring about the sex-biased differences in liver autophagy are still unknown. In this work, we found that autophagic genes variably expresses in the steroidogenic tissues, mostly abundant in liver, and is influenced by the individual's sexuality. Starvation-induced autophagy in a time-dependent female-dominated manner, and upon starvation, a strong gender responsive circulating steroid-HK2 relation was observed, which highlighted the importance of estrogen in autophagy regulation. This was further confirmed by the enhanced or suppressed autophagy upon estrogen addition (male) or blockage (female), respectively. In addition, we found that estrogen proved to be the common denominator between stress management, glucose metabolism, and autophagic action in female fish. To understand further, we used estrogen receptor (ER)α- and ER-β2-knockout (KO) medaka and found ER-specific differences in sex-biased autophagy. Interestingly, starvation resulted in significantly elevated mTOR transcription (compared with control) in male ERα-KO fish while HK2 and ULK activation was greatly decreased in both KO fish in a female oriented fashion. Later, ChIP analysis confirmed that, NRF2, an upstream regulator of mTOR, only binds to ERα, while both ERα and ERβ2 are effectively pulled down the HK2 and LC3. FIHC data show that, in both ER-KO fish, LC3 nuclear-cytoplasmic transport and its associated pathways involving SIRT1 and DOR were greatly affected. Cumulatively, our data suggest that, ERα-KO strongly affected the early autophagic initiation and altered the LC3 nuclear-cytoplasmic translocation, thereby influencing the sex-biased final autophagosome formation in medaka. Thus, existence of steroid responsive autophagy regulatory-switches and sex-biased steroid/steroid receptor availability influences the gender-skewed autophagy. Expectedly, this study may furnish newer appreciation for gender-specific medicine research and therapeutics.

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

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

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