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No Need for the Nuclear Middle Man
Estrogen suppresses the transcription of genes that encode enzymes involved in lipid synthesis in the liver. The estrogen receptor α (ERα) can initiate downstream signaling from the plasma membrane or can translocate to the nucleus to alter gene expression. Using mice engineered with ERα that could not bind DNA or transcriptional activators and could only signal from the plasma membrane (membrane-localized ERα) or that were entirely null for ERα, Pedram et al. showed that activation of only the membrane-localized ERα was sufficient to decrease cholesterol synthesis in murine hepatocytes. Activation of membrane-localized ERα with either estrogen or a pharmacological agonist triggered the phosphorylation of the transcription factor Srebf1 by AMP-activated kinase (AMPK), which prevented Srebf1 cleavage by the protease S1P, nuclear translocation, and the transcription of its target genes. Activation of membrane-localized ERα counteracted the insulin-stimulated synthesis of fatty acids in the liver. Thus, even without the ability to directly regulate transcription, membrane-localized ERα can indirectly inhibit gene expression and influence metabolism.
