Episodic Liver Injuries Lead to a Long-Term Liver Damage and Molecular Changes

Abstract

The liver is the biggest organ in the body that contributes to many vital functions like metabolism, immunity, digestion, and detoxification. The liver is not only capable of regenerating itself after a chemical or surgical injury. It is considered the sewage treatment and the recycling system of the body. Despite these remarkable abilities, chronic liver diseases are well known as one of the biggest threats to public health in the last decade – with their continued expansion across the world. While current models of liver regeneration after an injury have been critical in analyzing some of the liver’s regenerative processes, few models have demonstrated the effect of repeated liver injuries on liver damage and regeneration. To this end, this study created two novel repeated injuries and recovery models - genetic and physiological -in mice to examine how these episodic injuries sensitize the liver to further damage and nonalcoholic fatty liver disease (NAFLD). Both models used repetitive YAP activation to promote these injuries, then allowing for different recovery periods before collecting liver samples for analysis. In the genetic model, Doxycycline (Dox) initiated the injury. In contrast, the physiological model was described by performing partial hepatectomy(PHx) that mimics high-fat diet (HFD) induced injury. The study data showed that repetitive injury increased NAFLD levels in both models. Furthermore, this research expands on the development of NAFDL, which involves decompensation, liver failure, and hepatocellular carcinoma and is accompanied by molecular changes in the hepatocytes and other liver cells, modulating the -inflammation and injury processes. By understanding that these changes are a result of the up-or-down-regulation of the respective genes in the liver cell, this study observed the molecular changes of YAP target genes TEAD1, TEAD4, and JADE 3 to investigate their role in promoting persistence changes during liver recovery. This was done by performing qPCR and evaluating these transcription factors' expression levels during the repetitive injury and recovery periods. The results showed that TEAD4 is expressed during recovery even when YAP is not activated. These results suggest that initial liver injury promotes intrinsic memory so the liver can respond faster to repeated injuries. This finding may carry significant value for public health and liver research, as it may guide research to develop a new therapy that may prevent the progression of liver injury.