TRIB1 regulates liver regeneration by antagonizing the NRF2-mediated antioxidant response. 2023

Xinyue Sun, and Shuai Wang, and Xiulian Miao, and Sheng Zeng, and Yan Guo, and Anqi Zhou, and Ying Chen, and Yifei Chen, and Fangqiao Lv, and Zhiwen Fan, and Yutong Wang, and Yong Xu, and Zilong Li
State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China.

Robust regenerative response post liver injuries facilitates the architectural and functional recovery of the liver. Intrahepatic redox homeostasis plays a key role in liver regeneration. In the present study, we investigated the contributory role of Tribbles homolog 1 (Trib1), a pseudokinase, in liver regeneration and the underlying mechanism. We report that Trib1 expression was transiently down-regulated in animal and cell models of liver regeneration. Further analysis revealed that hepatocyte growth factor (HGF) repressed Trib1 transcription by evicting liver X receptor (LXRα) from the Trib1 promoter. Knockdown of Trib1 enhanced whereas over-expression of Trib1 suppressed liver regeneration after partial hepatectomy in mice. Of interest, regulation of liver regenerative response by Trib1 coincided with alterations of intracellular ROS levels, GSH levels, and antioxidant genes. Transcriptional assays suggested that Trib1 influenced cellular redox status by attenuating nuclear factor erythroid 2-related factor 2 (Nrf2) activity. Mechanistically, Trib1 interacted with the C-terminus of Nrf2 thus masking a potential nuclear localization signal (NLS) and blocking nuclear accumulation of Nrf2. Finally, correlation between Trib1 expression, Nrf2 nuclear localization, and cell proliferation was identified in liver specimens taken from patients with acute liver failure. In conclusion, our data unveil a novel pathway that depicts Trib1 as a critical link between intracellular redox homeostasis and cell proliferation in liver regeneration.

UI MeSH Term Description Entries
D008099 Liver A large lobed glandular organ in the abdomen of vertebrates that is responsible for detoxification, metabolism, synthesis and storage of various substances. Livers
D008115 Liver Regeneration Repair or renewal of hepatic tissue. Liver Regenerations,Regeneration, Liver,Regenerations, Liver
D006498 Hepatectomy Excision of all or part of the liver. (Dorland, 28th ed) Hepatectomies
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D000975 Antioxidants Naturally occurring or synthetic substances that inhibit or retard oxidation reactions. They counteract the damaging effects of oxidation in animal tissues. Anti-Oxidant,Antioxidant,Antioxidant Activity,Endogenous Antioxidant,Endogenous Antioxidants,Anti-Oxidant Effect,Anti-Oxidant Effects,Anti-Oxidants,Antioxidant Effect,Antioxidant Effects,Activity, Antioxidant,Anti Oxidant,Anti Oxidant Effect,Anti Oxidant Effects,Anti Oxidants,Antioxidant, Endogenous,Antioxidants, Endogenous
D017346 Protein Serine-Threonine Kinases A group of enzymes that catalyzes the phosphorylation of serine or threonine residues in proteins, with ATP or other nucleotides as phosphate donors. Protein-Serine-Threonine Kinases,Serine-Threonine Protein Kinase,Serine-Threonine Protein Kinases,Protein-Serine Kinase,Protein-Serine-Threonine Kinase,Protein-Threonine Kinase,Serine Kinase,Serine-Threonine Kinase,Serine-Threonine Kinases,Threonine Kinase,Kinase, Protein-Serine,Kinase, Protein-Serine-Threonine,Kinase, Protein-Threonine,Kinase, Serine-Threonine,Kinases, Protein Serine-Threonine,Kinases, Protein-Serine-Threonine,Kinases, Serine-Threonine,Protein Kinase, Serine-Threonine,Protein Kinases, Serine-Threonine,Protein Serine Kinase,Protein Serine Threonine Kinase,Protein Serine Threonine Kinases,Protein Threonine Kinase,Serine Threonine Kinase,Serine Threonine Kinases,Serine Threonine Protein Kinase,Serine Threonine Protein Kinases
D047908 Intracellular Signaling Peptides and Proteins Proteins and peptides that are involved in SIGNAL TRANSDUCTION within the cell. Included here are peptides and proteins that regulate the activity of TRANSCRIPTION FACTORS and cellular processes in response to signals from CELL SURFACE RECEPTORS. Intracellular signaling peptide and proteins may be part of an enzymatic signaling cascade or act through binding to and modifying the action of other signaling factors. Intracellular Signaling Peptides,Intracellular Signaling Proteins,Peptides, Intracellular Signaling,Proteins, Intracellular Signaling,Signaling Peptides, Intracellular,Signaling Proteins, Intracellular
D051267 NF-E2-Related Factor 2 A basic-leucine zipper transcription factor that was originally described as a transcriptional regulator controlling expression of the BETA-GLOBIN gene. It may regulate the expression of a wide variety of genes that play a role in protecting cells from oxidative damage. Nfe2l2 Protein,Nuclear Factor (Erythroid-Derived 2)-Like 2 Protein,Nuclear Factor E2-Related Factor 2,NF E2 Related Factor 2,Nuclear Factor E2 Related Factor 2
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus

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