Nuclear receptor ERRγ acts as a key transcriptional regulator of hepatic LCN2 expression in CCl4-induced acute liver injury.

Estrogen-related receptor γ (ERRγ) is a nuclear receptor and transcription factor that plays an important role in liver metabolism by regulating the transcription of genes involved in inflammation, alcohol metabolism, and iron metabolism. Lipocalin 2 (LCN2) is a secreted protein that regulates inflammation, immune response, and iron homeostasis and is involved in liver injury. However, the transcriptional regulation of LCN2 in the liver remains largely unknown. Here, we showed that ERRγ is a critical transcriptional regulator of the hepatic LCN2 gene in carbon tetrachloride (CCl4)-induced acute liver injury. CCl4 treatment significantly increased hepatic ERRγ and LCN2 gene expression by inducing interleukin-6 (IL-6) expression in mice. Interestingly, ERRγ overexpression increased LCN2 gene expression and secretion in the livers of mice. Conversely, mice with the liver-specific knockout of ERRγ (ERRγ-LKO) exhibited significantly decreased CCl4-induced LCN2 gene expression in the liver. Moreover, IL-6 treatment increased LCN2 expression and secretion in the livers of wild-type mice, which was significantly attenuated in ERRγ-LKO mice. Furthermore, deletion and mutation analyses revealed that ERRγ directly binds to ERR-response elements in the LCN2 promoter, modulating LCN2 gene transcription; these data were confirmed by a chromatin immunoprecipitation assay. Finally, administering GSK5182, an inverse agonist of ERRγ, significantly reduced the CCl4-induced levels of LCN2 mRNA and protein in the liver. These findings suggest that ERRγ is a previously unrecognized transcriptional regulator of LCN2 in CCl4-mediated acute liver injury.