Uterine glycolytic enzyme expression is affected by knockout of different estrogen receptor subtypes.

ABSTRACT

The estrogen signaling pathway via nuclear estrogen receptors (ER) α and ß is considered to be the master regulator of the cellular glucose metabolism in the uterus. While in vivo animal studies have demonstrated that 17ß-estradiol (E2) treatment increases the expression levels and activities of several glycolytic enzymes in the uterus, the specific ER subtype-dependent regulation of key glycolytic enzymes in the uterus has not been experimentally verified. In this study, the localization of ERα and ERß in human and mouse endometria were evaluated using immunohistology. Given that ERα and ERß are not functionally equivalent, ERα, ERß and ERαß knockout (ERα-/-, ERß-/- and ERαß-/-) mice were utilized to determine the expression pattern of glycolytic enzymes in the uterus. It was found that the level of ERα was higher than that of ERß in the human and mouse endometrial epithelial and stromal cells, and both receptors were downregulated by E2 treatment in the mouse uterus. The expression of the hexokinase 1 and GAPDH was increased in ERα-/- and ERß-/- mice compared with wild-type controls. Increased phosphofructokinase expression was observed in ERα-/- and ERαß-/- mice, whereas increased pyruvate kinase isozyme M2 and pyruvate dehydrogenase expression was observed in ERß-/- and ERαß-/- mice. The findings indicated for the first time that while estrogen regulates ERα and ERß expression in the uterus, ERα and ERß selectively regulate uterine glycolytic enzyme expression during glycolysis. Additionally, the link between endometrial ER subtypes and glycolysis in women with polycystic ovary syndrome (PCOS) is discussed. The findings suggested that the E2-dependent ER-mediated regulation of glycolysis may be involved in the disturbance of the glucose metabolism in patients with PCOS with endometrial dysfunction.