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

Abstract

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.

“Oh, Dear We Are in Tribble”: An Overview of the Oncogenic Functions of Tribbles 1

“…TRIB1 also acts as a scaffold for the SAP18 (Sin3A-associated protein) and mSin3A interactions, which modulate the expression of MTTP (microsomal TG transfer protein) in the mouse liver, ultimately impacting lipid metabolism [42]. TRIB1 also has the capability to suppress liver regeneration by modulating redox homeostasis in hepatocytes via blockade of Nrf2 nuclear translocation [43]. TRIB1 genetic loci are also associated with liver function in terms of certain enzymes' secretion, such as alanine transaminase (ALT), alkaline phosphatase (ALP), and γ-glutamyl transferase (GGT), which are commonly used as markers of certain liver ailments, suggesting it to be a genetic trait that might be inherited among humans [55].…”