Nuclear Receptor Car-Er Alpha Signaling Regulates The Estrogen Sulfotransferase Gene In The Liver

Estrogen sulfotransferase (SULT1E1) inactivates estrogen and regulates its metabolic homeostats. Whereas SULT1E1 is expressed low in the liver of adult mice, it is induced by phenobarbital (PB) treatment or spontaneously in diabetic livers via nuclear receptors. Utilizing constitutive active/ androstane receptor (CAR) KO, estrogen receptor alpha (ER alpha KO, phosphorylation-blocked ER alpha S216A KI mice, it is now demonstrated that, after being activated by PB, CAR binds and recruits ER alpha onto the Sulte1 promoter for subsequent phosphorylation at Ser216. This phosphorylation tightens CAR interacting with ER alpha and to activates the promoter. Hepatic SULT1E1 mRNA levels are constitutively up-regulated in type 1 diabetic Akita mice; CAR spontaneously accumulates in the nucleus and activates the Sult1e1 promoter by recruiting phosphorylated ER alpha in the liver as observed with PB-induced livers. Thus, this CAR-phosphorylated ER alpha signaling enables these two nuclear receptors to communicate, activating the Sult1e1 gene in response to either PB or diabetes in mice. ER alpha phosphorylation may integrate CAR into estrogen actions, providing insights into understanding drug-hormone interactions in clinical therapy.