MEF2D Aggravates Hepatic Ischaemia-Reperfusion Injury by Transcriptionally Regulating CXCL1 Through Interacting With NAT10.

Background And Aims: Hepatic ischaemia-reperfusion injury (IRI), a common complication after hepatectomy and liver transplantation (LT), is a local sterile inflammatory response driven by innate immunity. Myocyte enhancer factor-2D (MEF2D) plays an important role in immune inflammatory response by transcriptionally activating or inhibiting gene expression, which is tightly associated with the pathogenic progression of hepatic disorders. However, the role of MEF2D in hepatic IRI is still unclear.

Methods: In this study, we measured MEF2D expression in liver tissue from LT patients, mice subjected to hepatic I/R surgery, and hepatocytes challenged by hypoxia/reoxygenation (H/R) treatment. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, tissue pathology, inflammatory cell infiltration, inflammatory factor expression and apoptosis were used to evaluate liver injury and function in these models. We further explored the regulatory mechanisms of MEF2D in the murine liver IRI model by using hepatocyte-specific MEF2D knockout mice in the liver IRI model.

Results: We observed that MEF2D expression was significantly up-regulated after liver I/R in both humans and mice. Notably, high MEF2D levels in human I/R liver specimens were strongly associated with poor prognosis after LT. Additionally, hepatocyte-specific MEF2D deficiency significantly alleviated I/R-induced liver injury and inhibited the hepatic inflammatory response and apoptosis. Mechanistically, MEF2D interacted with NAT10, which increased the transcriptional activity of MEF2D by acetylating its K279 lysine site, thereby promoting the transcription of CXCL1. Moreover, inhibition of NAT10 effectively ameliorated hepatic IRI.

Conclusions: NAT10-induced MEF2D acetylation aggravates hepatic IRI by positively regulating transcription of CXCL1 in hepatocytes, which provides a promising therapeutic target for hepatic IRI.