Accumulation of Nuclear PKM2 Promotes LPS/D-Gal-Induced Fulminant Liver Injury via Reduction of Pyruvate and Inactivation of CDK1

Background: Accumulating evidence indicates that metabolic events profoundly modulate the progression of various diseases. The pyruvate kinases catalyze the production of pyruvate and pyruvate kinase M2 (PKM2) is a unique isoform involved in the development of tumors. In the present study, the pathological significance of PKM2 has been investigated in mice with lipopolysaccharide/D-galactosamine (LPS/D-Gal)-induced fulminant liver injury. Methods: Fulminant liver injury was induced in mice by intraperitoneal injection of LPS/D-Gal, the level of nuclear PKM2, the activity of pyruvate kinase and the content of pyruvate were determined. To investigated the significance of PKM2/ pyruvate, the PKM2 modulator TEPP-46, DASA-58 or the cell permeable ethyl pyruvate (EP) was administered and the degree of hepatocyte apoptosis and liver damage were evaluated. In addition, phospho-antibody microarray was used to identify the underlying signaling pathways. Findings: LPS/D-Gal exposure increased the nuclear level of PKM2 but decreased the activity of pyruvate kinase and the content of pyruvate. Treatment with the PKM2 modulator TEPP-46 or supplementation with ethyl pyruvate (EP) suppressed LPS/D-Gal-induced liver damage. Interestingly, post-insult administration of TEPP-46, another PKM2 modulator DASA-58 or EP also resulted in beneficial outcomes. The phospho-antibody microarray analysis found that LPS/D-Gal induced inhibitory phosphorylation of cyclin dependent kinase 1 (CDK1), which was reversed by TEPP-46, DASA-58 or EP. In addition, the therapeutic benefits of TEPP-46 or EP were blunted by the CDK1 inhibitor Ro 3306. Interpretation: Our data suggests that LPS/D-Gal exposure-induced accumulation of nuclear PKM2, decline of pyruvate and inactivation of CDK1 might be a novel metabolic mechanism underlies the development of LPS/D-Gal-induced fulminant liver injury, PKM2/pyruvate might be a promising target for the pharmacological intervention of fulminant hepatocyte damage. Funding: This work was supported by the grants from the National Natural Science Foundation of China (No. 81871606) and the grant from Science and Technology Research Program of Chongqing Municipal Education Commission (No. KJQN201900435). Declaration of Interest: None to declare. Ethical Approval: The Ethics Committee of Chongqing Medical University approved all mouse experiments.