title: Estrogen reduces lipid content in the liver exclusively from membrane receptor signaling.
abstract: Estrogen induces signal transduction through estrogen receptor α (ERα), which localizes to both the plasma membrane and nucleus. Using wild-type mice, ERα knockout (ERKO) mice, or transgenic mice expressing only the ligand-binding domain of ERα exclusively at the plasma membrane (MOER), we compared the transcriptional profiles of liver tissue extracts after mice were injected with the ERα 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 ERα 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 ERα 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 ERα caused a metabolic phenotype that did not require nuclear ERα.
authors.affiliation: 1Department of Medicine, University of California, Irvine, Irvine, CA 92717, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Pedram
authors.forename: Mahnaz
authors.initials: M
authors.lastname: Razandi
authors.forename: Fiona
authors.initials: F
authors.lastname: O'Mahony
authors.forename: Harry
authors.initials: H
authors.lastname: Harvey
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Harvey
authors.forename: Ellis R
authors.initials: ER
authors.lastname: Levin
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000502:physiology*; D008055:Lipids / Q000032:analysis*; D008099:Liver / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens; D008055:Lipids; D011956:Receptors, Cell Surface; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D017868:Cyclic AMP-Dependent Protein Kinases; D000263:Adenylate Kinase