Health
Sustained activation of the DNA damage response in the liver after MASLD recovery
Background and purpose
Metabolic dysfunction-associated fatty liver disease (MASLD) and its more advanced form, metabolic dysfunction-associated steatohepatitis, have emerged as the most prevalent liver diseases worldwide. Lifestyle modification is currently the top priority of guideline-recommended management strategies for MASLD. However, it remains unclear what deleterious signals persist in MASLD even after disease remission. Therefore, we aimed to examine sustained changes in liver transcriptome profiles after this reversal.
method
Male C57BL/6J mice were divided into three groups: Western diet (WD) fed, chow (CD) fed, or diet reversal from WD to CD. After 16 weeks of feeding, we performed RNA sequencing on mouse livers and identified persistent changes characteristic of MASLD. Additionally, we utilized an RNA-seq database containing P53 knockout mouse and human MASLD samples fed a high-fat diet.
result
WD-induced MASLD caused sustained activation of the DNA damage response (DDR) and its primary transcription factor P53, long after resolution of the hepatic phenotype by dietary reversal. Elevated P53 levels strongly correlate with hepatocyte ballooning, an indicator of apoptotic activation, and thus may promote apoptosis and thereby exacerbate steatohepatitis associated with metabolic dysfunction. Furthermore, P53 knockout in mice downregulated the expression of apoptotic signaling in the liver. Mechanistically, P53 may regulate apoptosis by transcriptionally activating the expression of apoptosis-enhancing nuclease (AEN). Consistently, P53, AEN, and apoptotic processes all showed persistently elevated expression and strong intercorrelation in the liver after dietary reversal.
conclusion
The liver showed upregulation of DDR signaling and the P53-AEN apoptotic axis both during and after exposure to WD. Our findings provide new insights into the mechanisms of MASLD relapse and highlight DDR signaling as a promising target to prevent MASLD relapse.
sauce:
Reference magazines:
Zou, Z.-Y. others. (2024). Transcriptomic landscape analysis reveals sustained DNA damage response in metabolic dysfunction-associated steatohepatitis after dietary intervention. Journal of Clinical and Translational Hepatology. doi.org/10.14218/jcth.2024.00111.
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