Estrogen and estrogen receptors chauffeur the sex-biased autophagic action in liver.
Journal
Cell death and differentiation
ISSN: 1476-5403
Titre abrégé: Cell Death Differ
Pays: England
ID NLM: 9437445
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
26
08
2019
accepted:
20
05
2020
revised:
20
05
2020
pubmed:
3
6
2020
medline:
20
11
2021
entrez:
3
6
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32483382
doi: 10.1038/s41418-020-0567-3
pii: 10.1038/s41418-020-0567-3
pmc: PMC7566502
doi:
Substances chimiques
Estrogen Receptor alpha
0
Estrogens
0
Receptors, Thyroid Hormone
0
TOR Serine-Threonine Kinases
EC 2.7.11.1
Sirtuin 1
EC 3.5.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3117-3130Références
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