Persistent activation of the DNA damage response in the liver after MASLD reversal

Context and objectives

Steatotic liver disease associated with metabolic dysfunction (MASLD) and its more advanced form, steatohepatitis associated with metabolic dysfunction, have become the most prevalent liver diseases worldwide. Currently, lifestyle modification is the most recommended management strategy for MASLD. However, it remains unclear which harmful signals persist in MASLD even after disease remission. Thus, we sought to examine persistent changes in hepatic transcriptomic profiles following this reversal.

Methods

Male C57BL/6J mice were divided into three groups: Western diet feeding (WD), chow diet feeding (CD), or diet reversal from WD to CD. After 16 weeks of feeding, RNA sequencing was performed on the mice’s livers to identify persistent alterations characteristic of MASLD. Additionally, RNA sequencing databases containing P53 knockout mice fed a high-fat diet and human MASLD samples were used.

Results

DEO-induced MASLD triggered persistent activation of the DNA damage response (DDR) and its major transcription factor, P53, long after resolution of the hepatic phenotype by diet reversal. Elevated P53 levels could promote apoptosis, thereby exacerbating steatohepatitis associated with metabolic dysfunction, as they are strongly correlated with hepatocyte ballooning, an indicator of apoptosis activation. Furthermore, knockdown of P53 in mice resulted in downregulated expression of apoptosis signaling in the liver. Mechanistically, P53 can regulate apoptosis by transcriptionally activating the expression of apoptosis-enhancing nuclease (AEN). Consistently, P53, AEN, and the apoptosis process all showed consistently high expression and showed strong cross-correlation in the liver after diet reversal.

Conclusions

The liver demonstrated upregulation of DDR signaling and the P53-AEN apoptosis axis during and after WD exposure. Our results provide new insights into the mechanisms of MASLD relapse, highlighting DDR signaling as a promising target to prevent MASLD relapse.