Estrogen and estrogen receptors chauffeur the sex-biased autophagic action in liver
Estrogen and estrogen receptors chauffeur the sex-biased autophagic action in liver
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DOI：
10.1038/s41418-020-0567-3
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发表时间：
2020-06-01
影响因子：
12.4
通讯作者：
Ohta, Kohei
中科院分区：
文献类型：
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作者：
Mohapatra, Sipra;Chakraborty, Tapas;Ohta, Kohei
自噬或细胞自我消化是能量稳态、发育、分化和存活所必需的基本细胞过程。然而，导致肝脏自噬性别差异的内在因素尚不清楚。在这项工作中，我们发现自噬基因在类固醇生成组织中表达，主要在肝脏中表达，并受到个体性别的影响。饥饿诱导的自噬以时间依赖性的女性主导的方式，并在饥饿时，观察到强烈的性别反应循环类固醇-HK 2的关系，这突出了雌激素在自噬调节的重要性。这进一步证实了增强或抑制自噬后雌激素添加（男性）或阻断（女性），分别。此外，我们发现雌激素被证明是压力管理，葡萄糖代谢和自噬作用之间的共同点。为了进一步了解，我们使用雌激素受体（ER）α和ER-β 2-敲除（KO）青鳉，发现了性别偏向性自噬的ER特异性差异。有趣的是，饥饿导致雄性ER α-KO鱼中mTOR转录显著升高（与对照相比），而HK 2和ULK活化在两种KO鱼中以雌性定向的方式大大降低。后来，ChIP分析证实，mTOR的上游调节因子NRF 2仅与ER α结合，而ER α和ER β 2都被有效地拉下HK 2和LC 3。FIHC数据显示，在两种ER-KO鱼中，LC 3核质转运及其涉及SIRT 1和DOR的相关途径都受到了极大的影响。总的来说，我们的数据表明，ER alpha-KO强烈影响早期自噬启动并改变LC 3核质易位，从而影响青鳉中性别偏向的最终自噬体形成。因此，类固醇反应性自噬调节开关的存在和性别偏见的类固醇/类固醇受体的可用性影响性别偏斜的自噬。预期，这项研究可能会为性别特异性医学研究和治疗提供新的认识。
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)alpha- and ER-beta 2-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 ER alpha-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 ER alpha, while both ER alpha and ER beta 2 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, ER alpha-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.