Department of Pharmacology &Therapeutics, Faculty of Pharmacy and Drug Manufacturing, Pharos University in Alexandria, Alexandria, Egypt.
Department of Biochemistry, Medical Research Institute, Alexandria University, Alexandria, Egypt.
Eur J Pharmacol. 2020 Apr 15;873:173006. doi: 10.1016/j.ejphar.2020.173006. Epub 2020 Feb 8.
Estrogen and the estrogen receptors (ERs) are well-known regulators of several aspects of glucose and lipid metabolism. Meanwhile, the underlying mechanistic role of estrogens in regulating metabolic health remains largely unknown. Hence, the study was designed to tackle the possible contribution of the hepatic expression of miR-33, miR-21 and miR-34a and their target genes as the underlying mechanism of the metabolic effects of estrogen in ovariectomized rats. Forty female rats were ovariectomized (OVX), treated with estrogen and/or fulvestrant for 28 days and compared with untreated or treated sham operated rats. Estradiol amended the metabolic abnormalities in the OVX rats, witnessed by decreasing blood sugar, insulin and HOMA-IR as well as correcting the disrupted serum and hepatic lipids. Estradiol increased the hepatic expression of miR-33 and inhibited that of miR-34a and miR-21, leading to adjusting the gene expression and the protein level of their targets, sterol regulatory element-binding proteins-1c (SREBP-1c), fatty acid synthase (FASN), high mobility group (HMG) Box Transcription Factor 1 (HBP1) and Sirtuin 1 (SIRT1), receptively. However, estrogen had no significant effects on HBP1 protein. These effects were almost completely inhibited by fulvestrant, an estrogen receptor blocker, to the extent that fulvestrant had similar metabolic disorders to that of ovariectomization. In conclusion, estrogen replacement therapy in OVX females significantly ameliorated the metabolic derangements of insulin resistance, dyslipidemia and hepatic fat accumulation possibly via corrections of hepatic expression of miR-33 and miR-34a; effects that were mediated through the receptor-mediated signaling of ERs as confirmed by fulvestrant.
雌激素及其受体（ERs）是调节葡萄糖和脂质代谢几个方面的已知调节剂。同时，雌激素调节代谢健康的潜在机制作用在很大程度上仍然未知。因此，本研究旨在探讨肝脏中 miR-33、miR-21 和 miR-34a 的表达及其靶基因的可能贡献，作为雌激素对去卵巢大鼠代谢影响的潜在机制。40 只雌性大鼠被卵巢切除术（OVX），用雌激素和/或氟维司群治疗 28 天，并与未治疗或治疗的假手术大鼠进行比较。雌二醇纠正了 OVX 大鼠的代谢异常，表现为降低血糖、胰岛素和 HOMA-IR，并纠正了血清和肝脏脂质的紊乱。雌二醇增加了肝脏中 miR-33 的表达，并抑制了 miR-34a 和 miR-21 的表达，从而调节了它们的靶基因，固醇调节元件结合蛋白-1c（SREBP-1c）、脂肪酸合酶（FASN）、高迁移率族（HMG）盒转录因子 1（HBP1）和 Sirtuin 1（SIRT1）的基因表达和蛋白水平。然而，雌激素对 HBP1 蛋白没有显著影响。这些作用几乎完全被雌激素受体阻滞剂氟维司群抑制，以至于氟维司群对代谢紊乱的影响与卵巢切除术相似。总之，雌激素替代疗法对 OVX 雌性大鼠的代谢紊乱有显著改善作用，如胰岛素抵抗、血脂异常和肝脂肪堆积，可能是通过纠正肝脏中 miR-33 和 miR-34a 的表达；这些作用通过 ERs 的受体介导信号转导得到证实，如氟维司群。
