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.

自噬或细胞自我消化是能量稳态、发育、分化和生存必不可少的细胞过程。然而，导致肝脏自噬存在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不同，主要在肝脏中丰富，并且受个体性行为的影响。饥饿诱导的自噬以时间依赖的女性为主，饥饿时观察到强烈的性别响应循环类固醇-HK2 关系，这突出了雌激素在自噬调节中的重要性。雌激素添加（雄性）或阻断（雌性）时自噬的增强或抑制进一步证实了这一点。此外，我们发现雌激素被证明是雌性鱼的压力管理、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-β2-敲除 (KO) medaka 并发现性别偏见自噬中 ER 特异性差异。有趣的是，饥饿导致雄性 ERα-KO 鱼的 mTOR 转录显着升高（与对照相比），而HK2和 ULK 激活在两种 KO 鱼中都以女性为导向的方式大大降低。随后，ChIP 分析证实，mTOR 的上游调节因子 NRF2 仅与 ERα 结合，而 ERα 和 ERβ2 均被有效拉低 HK2 和 LC3。FIHC 数据显示，在 ER-KO 鱼中，LC3 核质转运及其涉及 SIRT1 和 DOR 的相关通路受到很大影响。累积起来，我们的数据表明，ERα-KO 强烈影响早期自噬起始并改变 LC3 核 - 细胞质易位，从而影响 medaka 中具有性别偏见的最终自噬体形成。因此，类固醇响应自噬调节开关和性别偏向的类固醇/类固醇受体可用性的存在会影响性别偏向的自噬。预计，