| First Author | Pedram A | Year | 2013 |
| Journal | Sci Signal | Volume | 6 |
| Issue | 276 | Pages | ra36 |
| PubMed ID | 23695162 | Mgi Jnum | J:260643 |
| Mgi Id | MGI:6141458 | Doi | 10.1126/scisignal.2004013 |
| Citation | Pedram A, et al. (2013) Estrogen reduces lipid content in the liver exclusively from membrane receptor signaling. Sci Signal 6(276):ra36 |
| abstractText | Estrogen induces signal transduction through estrogen receptor alpha (ERalpha), which localizes to both the plasma membrane and nucleus. Using wild-type mice, ERalpha knockout (ERKO) mice, or transgenic mice expressing only the ligand-binding domain of ERalpha exclusively at the plasma membrane (MOER), we compared the transcriptional profiles of liver tissue extracts after mice were injected with the ERalpha 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 ERalpha 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 ERalpha 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 ERalpha caused a metabolic phenotype that did not require nuclear ERalpha. |
