Tristetraprolin family of RNA binding proteins post-transcriptionally regulate inflammation and metabolic responses in the liver

Abstract

Abstract Tristetraprolin family of RNA binding proteins, including tristetraprolin (TTP), zinc finger protein 36 like 1 (ZFP36L1), and zinc finger protein 36 like 2 (ZFP36L2) regulate mRNA levels by binding to AU-rich elements on the 3′untranslated regions of specific mRNAs and enhancing their turnover. Global loss of TTP results in systemic inflammatory syndrome in mice; however, the physiological role of the other two TTP family members is unclear due to embryonic lethality of global knockout of ZFP36L1 and early post-natal death of global knockout of ZFP36L2. Here, using Cre-loxP technology, we independently and simultaneously (triple KO) deleted the three TTP family members in mouse liver and characterized the phenotype of the resulting mice strains using histopathological, immunohistochemical, clinical, and transcriptomic approaches. The triple KO mice exhibited chronic active peri-portal hepatitis, bile duct hyperplasia, and portal fibrosis. Immunohistochemically, increased numbers of T cells, B cells, macrophages, and neutrophils were detected within the peri-portal areas. Increased expression of heme-oxygenase-1, a marker of reactive oxygen species was also found. Clinically, serum levels of bile acids, bilirubin, and liver function enzymes were markedly elevated. Transcriptomic and bioinformatics analysis of liver RNA demonstrated novel potential liver specific inflammatory and metabolic mRNA targets of TTP family proteins that are post-transcriptionally regulated by TTP family proteins in both specific and redundant manner. In summary, our study provides strong evidence that TTP family of RNA binding proteins maintain immune and metabolic homeostasis in the liver.