Sumarac-Dumanovic Mirjana, Apostolovic Milica, Janjetovic Kristina, Jeremic Danka, Popadic Dusan, Ljubic Aleksandar, Micic Jelena, Dukanac-Stamenkovic Jelena, Tubic Aleksandra, Stevanovic Darko, Micic Dragan, Trajkovic Vladimir
Clinic for Endocrinology, Diabetes, and Diseases of Metabolism, Clinical Center of Serbia, Belgrade, Serbia; School of Medicine, University of Belgrade, Belgrade, Serbia.
School of Medicine, University of Belgrade, Belgrade, Serbia.
Mol Cell Endocrinol. 2017 Jan 15;440:116-124. doi: 10.1016/j.mce.2016.11.009. Epub 2016 Nov 11.
Autophagy, a process of controlled cellular self-digestion, could be involved in cyclic remodeling of the human endometrium. We investigated endometrial mRNA expression of 23 autophagy-related (ATG) genes and transcription factors in healthy controls (n = 12) and anovulatory polycystic ovary syndrome (PCOS) patients (n = 24), as well as in their subgroup (n = 12) before and after metformin treatment. The mRNA levels of transcription factor forkhead box protein O1 (FOXO1) and several molecules involved in autophagosome formation (ATG13, RB1-inducible coiled-coil 1), autophagosome nucleation (ATG14, beclin 1, SH3-domain GRB2-like endophilin B1), autophagosome elongation (ATG3, ATG5, γ-aminobutyric acid receptor-associated protein - GABARAP), and delivery of ubiquitinated proteins to autophagosomes (sequestosome 1), were significantly reduced in anovulatory PCOS compared to healthy endometrium. Free androgen index, but not free estrogen index, insulin levels, or body mass index, negatively correlated with the endometrial expression of ATG3, ATG14, and GABARAP in PCOS patients. Treatment of PCOS patients with metformin (2 g/day for 3 months) significantly increased the endometrial mRNA levels of FOXO1, ATG3, and UV radiation resistance-associated gene. These data suggest that increased androgen availability in PCOS is associated with metformin-sensitive transcriptional downregulation of endometrial autophagy.
自噬是一种受调控的细胞自我消化过程，可能参与人类子宫内膜的周期性重塑。我们研究了健康对照组（n = 12）和无排卵性多囊卵巢综合征（PCOS）患者（n = 24）及其亚组（n = 12）在二甲双胍治疗前后23个自噬相关（ATG）基因和转录因子的子宫内膜mRNA表达。与健康子宫内膜相比，无排卵性PCOS患者中，转录因子叉头框蛋白O1（FOXO1）以及参与自噬体形成（ATG13、RB1诱导性卷曲螺旋1）、自噬体成核（ATG14、贝克林1、SH3结构域GRB2样内吞蛋白B1）、自噬体延伸（ATG3、ATG5、γ-氨基丁酸受体相关蛋白 - GABARAP）和泛素化蛋白向自噬体传递（聚集体蛋白1）的几种分子的mRNA水平显著降低。在PCOS患者中，游离雄激素指数而非游离雌激素指数、胰岛素水平或体重指数与ATG3、ATG14和GABARAP的子宫内膜表达呈负相关。用二甲双胍（2 g/天，共3个月）治疗PCOS患者可显著提高FOXO1、ATG3和紫外线抗性相关基因的子宫内膜mRNA水平。这些数据表明，PCOS中雄激素可用性增加与子宫内膜自噬的二甲双胍敏感型转录下调有关。
