Metabolic benefits of 17α-estradiol in liver are partially mediated by ERβ in male mice.
Metabolic benefits of 17α-estradiol in liver are partially mediated by ERβ in male mice.
复制标题
17α-雌二醇在肝脏中的代谢益处部分由雄性小鼠的 ERβ 介导。
DOI：
10.1101/2023.03.25.534216
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Stout,MichaelB
中科院分区：
文献类型：
--
作者：
Mondal,SamimAli;Mann,ShivaniN;vanderLinden,Carl;Sathiaseelan,Roshini;Kamal,Maria;Das,Snehasis;Bubak,MatthewP;Logan,Sreemathi;Miller,BenjaminF;Stout,MichaelB
代谢功能障碍是几种慢性疾病的基础。饮食干预可以逆转代谢下降和延缓衰老，但保持顺从是困难的。17α-雌二醇（17α-E2）治疗可改善雄性小鼠的代谢参数并延缓衰老，而不会诱导显著的雌性化。我们最近报道，雌激素受体α是雄性小鼠中17α-E2介导的大多数益处所必需的，但17α-E2也减弱了肝脏中的纤维化，这是由表达雌激素受体β（ERβ）的肝星状细胞（HSC）调节的。目前的研究试图确定17α-E2介导的对全身和肝脏代谢的益处是否是ERβ依赖性的。我们发现，17α-E2治疗逆转了雄性和雌性小鼠的肥胖和相关的全身代谢后遗症，但这在雌性而非雄性ERβKO小鼠中被部分阻断。雄性小鼠中的ERβ消融减弱了17α-E2介导的对肝硬脂酰辅酶A去饱和酶1（SCD 1）和转化生长因子β1（TGF-β1）产生的益处，这在HSC活化和肝纤维化中起关键作用。我们还发现，17α-E2处理抑制了培养的肝细胞和肝星状细胞中SCD 1的产生，表明17α-E2直接在两种细胞类型中发出信号，以抑制脂肪变性和纤维化的驱动因素。我们得出结论，雌激素受体β部分控制17α-E2介导的雌性小鼠（而非雄性小鼠）全身代谢调节的益处，并且17α-E2可能通过HSC中的雌激素受体β发出信号以减弱促纤维化机制。
Metabolic dysfunction underlies several chronic diseases. Dietary interventions can reverse metabolic declines and slow aging but remaining compliant is difficult. 17α-estradiol (17α-E2) treatment improves metabolic parameters and slows aging in male mice without inducing significant feminization. We recently reported that estrogen receptor α is required for the majority of 17α-E2-mediated benefits in male mice, but that 17α-E2 also attenuates fibrogenesis in liver, which is regulated by estrogen receptor β (ERβ)-expressing hepatic stellate cells (HSC). The current studies sought to determine if 17α-E2-mediated benefits on systemic and hepatic metabolism are ERβ-dependent. We found that 17α-E2 treatment reversed obesity and related systemic metabolic sequela in both male and female mice, but this was partially blocked in female, but not male, ERβKO mice. ERβ ablation in male mice attenuated 17α-E2-mediated benefits on hepatic stearoyl-coenyzme A desaturase 1 (SCD1) and transforming growth factor β1 (TGF-β1) production, which play critical roles in HSC activation and liver fibrosis. We also found that 17α-E2 treatment suppresses SCD1 production in cultured hepatocytes and hepatic stellate cells, indicating that 17α-E2 directly signals in both cell-types to suppress drivers of steatosis and fibrosis. We conclude that ERβ partially controls 17α-E2-mediated benefits on systemic metabolic regulation in female, but not male, mice, and that 17α-E2 likely signals through ERβ in HSCs to attenuate pro-fibrotic mechanisms.