Repeated toxic injuries of murine liver are tolerated through minute steatosis and mild inflammation

 

The liver has a remarkable capacity to regenerate and thus compensates for repeated injuries through toxic chemicals, drugs, alcohol, or malnutrition for decades. However, how and when tolerable damaging insults alternate the liver is still largely unknown. Over ten weeks, we induced repeated liver injuries in a mouse model by injecting carbon tetrachloride (CCl4) twice a week. We lost 10% of the study animals within the first six weeks, which was accompanied by a steady deposition of extracellular matrix (ECM) regardless of the metabolic activity of the liver. From week six onwards, all mice survived, and in these mice, ECM deposition was rather reduced, suggesting ECM remodeling as a liver response contributes to better coping with repeated injuries. The data of time-resolved paired transcriptome and proteome profiling of 18 mice were subjected to multi-level network inference, using Knowledge guided Multi-Omics Network inference (KiMONo), which identified multi-level key markers exclusively associated with the injury-tolerant liver response. Interestingly, cancer and inflammation pathways were upregulated and validated using independent data sets compiled of 1034 samples from publicly available human cohorts. A yet undescribed link to lipid metabolism in this damage-tolerant phase was identified and confirmed by immunostaining of lipid droplets (steatosis). We identified week six as a critical switching point in the liver response program from an acute response that fosters ECM accumulation, to a tolerant “survival” phase with pronounced deposition of small lipid droplets that potentially protect against repetitive injury with toxic chemicals.

Publication History

Article published online:
18 January 2023

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