Researchers have recently unearthed pivotal insights into the molecular mechanisms underlying liver injury and its potential links with kidney disease. The new study, which investigates the gene expression in a model of carbon tetrachloride (CCl4)-induced acute liver injury, has been a significant advancement in our understanding of the pathogenesis of these conditions. Fibroblast growth factor 23 (FGF23) is an osteocyte- and osteoblast-derived hormone that primarily regulates phosphate and vitamin D metabolism. Circulatory FGF23 levels are abnormally increased in pathological conditions like acute or chronic kidney injury, resulting in disease progression as well as increased rates of morbidity and mortality.1 However, FGF23 production in acute liver injury is not fully investigated.

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.

Reference

Images

Image title: CCl₄-induced acute liver injury increases FGF23 gene expression and secretion in mouse liver through ERRγ.

Image caption: CCl4-induced acute liver injury increases FGF23 gene expression and secretion in mouse liver through ERRγ. (A, B) Quantitative PCR analysis of total RNA obtained from the livers of mice injected with CCl4 (1 mL/kg body weight of 10% CCl4 dissolved in corn oil) for 6 h (n = 5 per group). (C–F) WT and ERRγ-LKO mice were injected with CCl4 for 6 h (n = 5 per groups). (C) Quantitative PCR analysis of total RNA isolated from livers. (D) Representative images of FGF23 immunohistochemical analysis in liver sections. (E) Representative in vivo images of hepatic FGF23 promoter WT-luciferase (Ad-FGF23-luc) activity in WT and ERRγ-LKO mice injected with or without CCl4 (n = 4 for WT-Con and ERRγ-LKO Con; n = 6 for WT-CCl4 and ERRγ-LKO CCl4 group). (F) Plasma FGF23 levels measured by ELISA. (G–I) WT mice were injected with CCl4 in the presence or the absence of GSK5182 and sacrificed after 6 h (n = 5 per group). (G) Quantitative PCR analysis of total RNA isolated from liver. (H) Representative images of FGF23 immunohistochemical analysis in liver sections. (I) Plasma FGF23 levels measured by ELISA. (J) Schematic diagram of ERRγ-mediated hepatic FGF23 gene expression and secretion in CCl4-induced acute liver injury. Data indicate mean ± SEM values. Data in (A) and (B) were analyzed by two-tailed Student's t test. Data in C, E, F, G and I were analyzed by ordinary one-way ANOVA with Tukey's multiple comparisons test. Significance levels denoted as ∗P < 0.05; ∗∗∗P < 0.001; n.s., not significant.

Image credit: The authors

Image link: https://ars.els-cdn.com/content/image/1-s2.0-S2352304222001775-gr1_lrg.jpg

License type: CC BY

Funding information

The National Research Foundation (NRF) basic science research program Korean government (Ministry of Science and ICT),

Republic of Korea (2020R1A6A3A01096145, 2020) (NRF-2019R1 C1C1005319, 2019) (NRF-2017R1A6A3A04006167, 2017) (NRF-2020R1A2C3006952, 2020) (NRF2021R1A2C3004923, 2021),

The Federal Ministry of Education and Research-Liver Systems Medicine Program of the

Stiftung für Biomedizinische Alkoholforschung, Germany (PTJ-031L0043).

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