In a study published in the journal of Genes & Diseases, a team of researchers from Chonnam National University and the Korea Research Institute of Bioscience and Biotechnology unveiled important insights into liver injury and its underlying molecular mechanisms. They discovered that CCl4 injections triggered a surge in pro-inflammatory cytokine interleukin-6 (IL6) mRNA in liver tissues, leading to an elevated presence of liver injury markers, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), in the blood plasma. Interestingly, kidney tissues were unaffected, with kidney injury markers, blood urea nitrogen (BUN) and creatinine, remaining stable.
The study builds on earlier findings, which showed that the estrogen-related receptor gamma (ERRγ) transcriptionally regulates the fibroblast growth factor 23 (FGF23) gene expression in the liver in response to folic acid-induced acute kidney injury (FA-AKI). The current research reveals ERRγ's crucial role as an upstream regulator of hepatic FGF23 gene expression following CCl4-induced acute liver injury. This was demonstrated by the noticeable reduction in hepatic ERRγ and FGF23 mRNA expression in ERRγ-LKO mice compared to CCl4-injected control mice. The team used an innovative approach involving a mouse FGF23 promoter luciferase construct fused with adenovirus (Ad-FGF23-luc) to discern the molecular mechanism governing ERRγ-regulated FGF23 gene expression in response to CCl4-induced acute liver injury. In vivo imaging showed enhanced hepatic FGF23 promoter activity in CCl4-injected mice, underscoring the ERRγ's direct binding with the FGF23 promoter. The use of a pharmacological ERRγ inhibitor, GSK5182, further supported these findings by significantly reducing CCl4-induced hepatic ERRγ and FGF23 mRNA expression. The results underscore ERRγ's central role in the regulation of hepatic FGF23 production during CCl4-induced acute liver injury, suggesting that inhibiting ERRγ signaling could be a potential strategy for reducing abnormal circulatory FGF23 levels in acute liver injuries. These findings have profound implications for our understanding and potential treatment of liver and kidney injuries.
In conclusion, this research provides vital insights into the molecular underpinnings of acute liver injury and its connection to kidney disease. It also lays the groundwork for future studies to potentially develop new therapeutic strategies targeting ERRγ to prevent or treat liver and kidney injuries.
Jung, Y. S., et al. (2022). Acute liver injury induces expression of FGF23 in hepatocytes via orphan nuclear receptor ERRγ signaling. Genes & Diseases. doi.org/10.1016/j.gendis.2022.06.003.