Glucose and fatty acid metabolism involved in the protective effect of metformin against ulipristal-induced endometrial changes in rats

Marwa S Hamza,Eman Ramadan,Salama A Salama

doi:10.1038/s41598-021-88346-w

Marwa S Hamza, Eman Ramadan + Show 1 more

Open Access

https://doi.org/10.1038/s41598-021-88346-w

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Abstract

Ulipristal acetate (UPA) is effective in the treatment of uterine fibroids. However, its clinical use is hampered by the development of pathologic progesterone receptor modulator-associated endometrial changes (PAECs). The current study was designed to test the hypothesis that UPA-induced PAECs are associated with deranged expression of some metabolic genes. In addition, metformin can mitigate UPA-induced PAECs through modulating the expression of these genes. In the present study, twenty-eight female non-pregnant, nulligravid Wistar rats were treated with UPA (0.1 mg/kg/day, intragastric) and/or metformin (50 mg/kg/day, intragastric) for 8 weeks. Our results demonstrated that co-treatment with metformin significantly reduced UPA-induced PAECs. In addition, co-treatment with metformin and UPA was associated with significant increase in the Bax and significant reduction in Bcl-2, PCNA, Cyclin-D1and ER-α as compared to treatment with UPA alone. Furthermore, treatment with UPA alone was associated with deranged expression of 3-phosphoglycerate dehydrogenase (3-PHGDH), glucose-6-phosphate dehydrogenase (G6PD), transketolase (TKT), fatty acid synthase (FAS) and CD36. Most importantly, co-treatment with metformin markedly reduced UPA-induced altered expression of these metabolic genes in endometrial tissues. In conclusion, UPA-induced PAECs are associated with altered expression of genes involved in cell proliferation, apoptosis, estrogen receptor, glucose metabolism and lipid metabolism. Co-treatment with metformin abrogated UPA-induced PAECs most likely through the modulation of the expression of these genes.

Highlights

Ulipristal acetate (UPA) is effective in the treatment of uterine fibroids
Co-treatment with metformin markedly reduced the average weight of uteri and the uteri weight/body weight ratio by 32% and 35% as compared to animals treated with UPA alone (P < 0.05, Fig. 1)
To determine whether UPA-induced endometrial changes are accompanied by alteration in the endometrial metabolism, we examined the expression of 3-Phosphoglycerate dehydrogenase (3-PHGDH), the first rate-limiting enzyme of serine synthesis which is frequently overexpressed in proliferating tissues. 3-phosphoglycerate dehydrogenase (3-PHGDH) overexpression directs glucose metabolism towards serine synthesis to promote cell p roliferation[31]

Summary

Introduction

Its clinical use is hampered by the development of pathologic progesterone receptor modulator-associated endometrial changes (PAECs). Metformin can mitigate UPA-induced PAECs through modulating the expression of these genes. Co-treatment with metformin markedly reduced UPA-induced altered expression of these metabolic genes in endometrial tissues. UPA-induced PAECs are associated with altered expression of genes involved in cell proliferation, apoptosis, estrogen receptor, glucose metabolism and lipid metabolism. Co-treatment with metformin abrogated UPA-induced PAECs most likely through the modulation of the expression of these genes. Ulipristal acetate (UPA) is a selective progesterone receptor modulator (SPRM). It has tissue selective, mixed progesterone agonist and antagonist effects in myometrial and endometrial tissues[1,2]. Previous work from our group and others demonstrated that sex hormones and their cognate receptors regulate endometrial m etabolism[16,17]

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