Estrogen Reduces Lipid Content in the Liver Exclusively from Membrane Receptor Signaling

Estrogen induces signal transduction through estrogen receptor alpha (ER alpha), which localizes to both the plasma membrane and nucleus. Using wild-type mice, ER alpha knockout (ERKO) mice, or transgenic mice expressing only the ligand-binding domain of ER alpha exclusively at the plasma membrane (MOER), we compared the transcriptional profiles of liver tissue extracts after mice were injected with the ERa agonist propyl-pyrazole-triol (PPT). The expression of many lipid synthesis-related genes was comparably decreased in livers from MOER or wild-type mice but was not suppressed in ERKO mice, indicating that only membrane-localized ER alpha was necessary for their suppression. Cholesterol, triglyceride, and fatty acid content was decreased only in livers from wild-type and MOER mice exposed to PPT, but not in the livers from the ERKO mice, validating the membrane-driven signaling pathway on a physiological level. PPT-triggered activation of ER alpha at the membrane induced adenosine monophosphate-activated protein kinase to phosphorylate sterol regulatory element-binding factor 1 (Srebf1), preventing its association with and therefore its proteolytic cleavage by site-1 protease. Consequently, Srebf1 was sequestered in the cytoplasm, preventing the expression of cholesterol synthesis-associated genes. Thus, we showed that inhibition of gene expression mediated by membrane-localized ER alpha caused a metabolic phenotype that did not require nuclear ER alpha.