RT Journal Article
SR Electronic
T1 Estrogen Reduces Lipid Content in the Liver Exclusively from Membrane Receptor Signaling
JF Science Signaling
JO Sci. Signal.
FD American Association for the Advancement of Science
SP ra36
OP ra36
DO 10.1126/scisignal.2004013
VO 6
IS 276
A1 Pedram, Ali
A1 Razandi, Mahnaz
A1 O’Mahony, Fiona
A1 Harvey, Harry
A1 Harvey, Brian J.
A1 Levin, Ellis R.
YR 2013
UL http://stke.sciencemag.org/content/6/276/ra36.abstract
AB 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.