FLUCTUATION OF ESTROGEN RECEPTOR TRANSCRIPTIONAL ACTIVITY IN PHYSIOLOGICAL CONDITIONS: FUNCTIONAL CONSEQUENCES

We have studied the dynamics of estrogen receptor (ER) activity in whole living animal through the application of in vivo imaging to the ERE-Luc mice, characterized by the hormone-inducible, generalized, expression of the ERE-driven luciferase gene. The analysis shows that ER transcriptional activity oscillates in time with an average period of 4.5 days and an amplitude which appears to be related to the amount and the chemical nature of the circulating estrogens. Particularly, the study in vivo shows that ER activity does not oscillate synchronously in every organ, and that the phasing of oscillation among organs changes in consideration to circulating estrogens; however, in liver we observe a pattern of activity that mimics the levels of estradiol in the bloodstream. We therefore investigated the physiological changes in hepatic tissue following the changes in ER activity at different phases of estrus cycle: at proestrus, when circulating estrogens are high, and metestrus, characterized by a low amount of circulating hormones. Livers of intact female mice, euthanized at the desired phase, were harvested, and a whole genome analysis of Estrogen Receptor binding sites and an expression profiling were carried out. Our results indicate that different levels of estradiol affect the ability of hepatic tissue to shift its metabolic state, since the hormonal fluctuations translates in a definite pattern of transcripts levels of genes involved particularly in lipid and cholesterol metabolism. Moreover, estrogenic action appears to play a central role on the control of hepatic energetic metabolism in other physiological states of female life cycle, such as puberty, pregnancy and menopause.