P53/miR-34a/SIRT1 positive feedback loop regulates the termination of liver regeneration

Background: The capacity of the liver to restore its architecture and function assures good prognoses of patients who suffer serious hepatic injury, cancer resection, or living donor liver transplantation. Only a few studies have shed light on the mechanisms involved in the termination stage of LR. Here, we attempt to further verify the role of the p53/miR-34a/SIRT1 positive feedback loop in the termination of liver regeneration and its possible relationship with liver cancer. Method: We performed partial hepatectomy (PH) in mice transfected with adenovirus (Ade) overexpressing P53 and adenovirus-associated virus (AAV) overexpressing miR-34a. LR was analyzed by liver weight/body weight, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and cell proliferation, and the related cellular signals were investigated. Bile acid (BA) levels during LR were analyzed by metabolomics of bile acids. Results: We found that the P53/miR-34a/SIRT1 positive feedback loop was activated in the late phase of LR. Overexpression of P53 or miR-34a terminated LR early and enhanced P53/miR-34a/SIRT1 positive feedback loop expression and its proapoptotic effect. T-β-MCA increased gradually during LR and peaked at 7 days after PH. T-β-MCA inhibited cell proliferation and promoted cell apoptosis via facilitating the P53/miR-34a/SIRT1 positive feedback loop during LR by suppressing FXR/SHP. The P53/miR-34a/SIRT1 positive feedback loop was abolished in HCC patients with P53 mutations. Conclusions: The P53/miR-34a/SIRT1 positive feedback loop plays an important role in the termination of LR. Our findings showed the molecular and metabolic mechanisms of LR termination and provide a potential therapeutic alternative for treating P53-wild-type HCC patients.