Cell-Cycle-Related and Expression Elevated Protein in Tumor Upregulates the Antioxidant Genes via Activation of NF-κB/Nrf2 in Acute Liver Injury

Background and aims: Cell-cycle-related and expression elevated protein in tumor (CREPT, also named RPRD1B) is highly expressed in tumors and functions to promote tumorigenesis. However, the role of CREPT in the pathophysiology of acute liver injury is limited. Here, we demonstrate that CREPT plays an essential role during acute liver injury.

Approach and results: Hepatocyte-specific CREPT knockout (CREPT^hep-/-) and CREPT^flox/flox mice were generated and subjected to the CCl₄ challenge for the acute (24 h) liver injury. The acute CCl₄ challenge triggered increased inflammation as well as liver injury, associated with stronger apoptotic and necroptotic cell death in CREPT^hep-/- mice. CREPT knockout down-regulated the expression of different genes involved in cell survival, inflammation and fibrosis under acute CCl₄ challenge conditions. Antioxidant enzymes such as superoxide dismutase 2 (Sod2) and ferritin heavy chain 1 (Fth1) are dramatically induced at 24 h post-CCl₄ treatment, but this induction is blocked by transcriptional inactivation of NF-κB/Nrf2, indicating that CREPT might promote hepatocyte survival in acute liver injury by participating in the transactivation of antioxidant genes.

Conclusions: These results elucidate the role of CREPT in acute liver injury and provide hints for future research on how CREPT might function in hepatocyte renewal.