Abstract: Objective To explore the potential mechanism by which NLRP3 mutation leads to its sustained activation and subsequent liver injury at the transcriptome level with an animal model of Nlrp3^T346M mutant transgenic mice. Methods Liver tissues from Nlrp3^T346M mice and their wild type (WT) littermates were subjected to transcriptome sequencing. Gene expression difference between the two groups was analyzed, followed by GO and KEGG enrichment analyses of the differentially expressed genes (DEGs). RT-qPCR was performed to verify the expression of relevant DEGs. Results Compared with WT group, a total of 258 DEGs were screened in the livers of Nlrp3^T346M mice, of which 197 were up-regulated and 61 were down-regulated. Enrichment analysis showed that the DEGs were mainly involved in circadian entrainment, as well as metabolic pathways of steroids, retinol and olefinic compounds,etc. RT-qPCR results showed mRNA expression trends of key DEGs in the circadian entrainment pathway, namely Cacna1h,Camk2b,Gnai1,Mtnr1a and Nos1ap were consistent with those observed in the transcriptome sequencing. Conclusions Sustained activation of NLRP3 in the liver tissue of Nlrp3^T346M mice may interfere with circadian entrainment, which in turn disrupts temporal regulation of downstream metabolism and hormone secretion, thus leads to liver injury.

Key words: Nlrp3 mutation, transgenic mouse, liver, RNA sequencing(RNA-seq), circadian entrainment