Estrogen Signaling in Metabolic Inflammation

Figure 2

Estrogen signaling occurs through both genomic and nongenomic mechanisms. In classical, genomic, estrogen signaling ERs act as ligand-activated transcription factors, activating or repressing target genes within hours of ligand binding. ERs are located as monomers in the cytoplasm in protein complexes involving heat-shock proteins and estrogen binding promotes their dissociation from this complex and ER dimerization. ER dimers bind directly to estrogen response elements of target gene promoters, or indirectly through interaction with other DNA-bound transcription factors. ERs also regulate gene expression in a ligand independent manner being activated downstream to growth factors binding to growth factor receptors, through the action of intracellular kinases or though the formation of heterodimers with different nuclear receptors (not shown). Genomic actions are modulated by cell-specific interaction with cofactors (coactivators or cosuppressors). Metabolic effects of estrogens seem to be largely mediated through nonnuclear ERs, either by interference with gene expression or by exerting nongenomic actions. This involves activation of ERs and G-protein-coupled ER located at the membrane or at extranuclear sites within seconds or minutes resulting in changes in Ca²⁺, K⁺, cAMP, and nitric oxide levels, activation of G protein-mediated events, and stimulation of different types of kinases such as extracellular-regulated kinases, phosphoinositide 3-kinases, mitogen-activated protein kinase, and c-Jun N-terminal kinases. E: estrogen; ER: estrogen receptor; ERE: estrogen-responsive element; ERK: extracellular-regulated kinase; GFR: growth factor receptor; GPER: G protein-coupled estrogen receptor; HSP: heat-shock protein; JNK: c-Jun N-terminal kinase; MAPK: mitogen-activated protein kinase; NO: nitric oxide; PI3K: phosphoinositide-3 kinase; TF: transcription factor.