GPER1/GIPC1-AMPKα signaling alleviates hepatic steatosis via regulating lipid metabolism and fatty acid oxidation-related gene expression: A novel target in MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is emerging as a major contributor to end-stage liver disease in the future. It is a sexually dimorphic disease characterized by hepatic steatosis, which is closely related to imbalances in lipid metabolism. The G-protein-coupled estrogen receptor 1 (GPER1) is an estrogen membrane receptor that has recently been implicated in MASLD. GAIP-interacting protein C-terminal 1 (GIPC1) is a scaffolding protein that regulates the expression and transport of cell-surface receptors. However, the roles of GPER1 and GIPC1 in MASLD pathogenesis remain unclear. In this study, we examined the molecular regulatory mechanisms of GPER1 and GIPC1 in MASLD using human liver samples, as well as animal and cellular models. We found that GPER1 activation increases the expression of proteins related to fatty acid oxidation (FAO), as well as phosphorylated AMP-activated protein kinase alpha (p-AMPKα) and GIPC1, which improves hepatocyte steatosis and lipid deposition. Silencing GIPC1 reduced the protective effect of the GPER1-specific agonist G1 against hepatic steatosis. Pretreating cells overexpressing GIPC1 with compound C or siAMPKα1α2 resulted in increased lipid droplet deposition and downregulated the expression of FAO-related proteins in hepatocytes to varying degrees. These results suggest that GIPC1 may be a downstream target of GPER1, which mediates GPER1's protective effect against MASLD, and the positive effects produced by GIPC1 depend on the activation of the AMPKα pathway. Furthermore, GIPC1 expression was significantly lower in the liver tissues of males than in those of females. In summary, mechanisms targeting GIPC1- AMPKα provide new targets for the prevention and treatment of MASLD.