Birmingham, AL -- Researchers have identified the receptor pathway used by estrogen to decrease liver injury after trauma and hemorrhage. The related report by Hsieh et al, "G protein-coupled receptor 30-dependent protein kinase A pathway is critical in nongenomic effects of estrogen in attenuating liver injury after trauma-hemorrhage," appears in the April issue of The American Journal of Pathology and is accompanied by a commentary.
Research has shown that estrogen improves host response after traumatic injury, but the cellular pathway used has been unknown. Estrogen directs cellular processes in two ways: by interacting with DNA to produce new protein or by binding cell surface receptors to initiate rapid protein signaling. Current data points to cell surface receptors in improving recovery from liver injury following soft-tissue trauma and major blood loss, but which receptor is responsible for producing this effect was not known until this study was performed.
Research directed by Irshad H. Chaudry at the University of Alabama at Birmingham sought to answer this question using an established rat model of liver injury and hemorrhage. They examined the cell surface receptor pathways by treating rats with a form of estrogen that cannot enter cells, thus acting only via cell surface interactions.
As expected, rats affected by trauma-hemorrhage released high levels of liver enzymes associated with liver damage. However, treatment with surface estrogen decreased the amount of enzymes released. Further, such treatment also maintained normal levels of cell-protective Bcl-2 and active protein kinase A, which were otherwise decreased by trauma-hemorrhage.
The researchers then examined two possible receptors, G protein-coupled receptor 30 (GPR30) and estrogen receptor-alpha, for their role in mediating estrogen's protective effects. Receptor expression on the cell surface was diminished by blocking protein production in cultured liver cells. Blockade of estrogen receptor-alpha had no effect on cells, but GPR30 silencing resulted in decreased Bcl-2 and active protein kinase A.
By identifying GPR30 and the downstream pathways (Bcl-2 and active protein kinase A) involved in estrogen's beneficial effects, Chaudry's group has provided new insights in resolving liver injury following tissue trauma and major blood loss. Specific activation of these protein pathways may provide novel therapeutics for treating trauma patients.