Deficiency of S100A9 Alleviates Sepsis-Induced Acute Liver Injury through Regulating AKT-AMPK-Dependent Mitochondrial Energy Metabolism

• Published in: International journal of molecular sciences Vol. 24; no. 3; p. 2112
• Main Authors: Zhang, Yanting, Wu, Feng, Teng, Fei, Guo, Shubin, Li, Huihua
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 20-01-2023; MDPI
• Subjects: acute liver injury; AKT protein; AMP-Activated Protein Kinases - metabolism; AMPK; Animals; Apoptosis; Calgranulin A - metabolism; Calgranulin B - genetics; Calgranulin B - metabolism; Cecum; Cytokines; Disease; Energy metabolism; Fatty acids; Immune response; Inflammation; Injury prevention; Intensive care units; Kinases; Liver; Liver - metabolism; Liver diseases; Medical prognosis; Metabolism; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondria - metabolism; mitochondrial energy metabolism; Mortality; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Respiration; S100A9; Sepsis; Sepsis - complications; Sepsis - metabolism; AMPK; mitochondrial energy metabolism; S100A9; sepsis; acute liver injury
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24032112

Acute liver injury (ALI) is recognized as a serious complication of sepsis in patients in intensive care units (ICUs). S100A8/A9 is known to promote inflammation and immune responses. However, the role of S100A8/A9 in the regulation of sepsis-induced ALI remains known. Our results indicated that S100A8/A9 expression was significantly upregulated in the livers of septic mice 24 h after cecal ligation and a puncture (CLP) operation. Moreover, S100A9-KO in mice markedly attenuated CLP-induced liver dysfunction and injury, promoting the AMPK/ACC/GLUT4-mediated increases in fatty acid and glucose uptake as well as the improvement in mitochondrial function and ATP production. In contrast, treatment with the AMPK inhibitor Compound C reversed the inhibitory effects of S100A9 KO on CLP-induced liver dysfunction and injury in vivo. Finally, the administration of the S100A9 inhibitor Paquinimod (Paq) to WT mice protected against CLP-induced mortality, liver injury and mitochondrial dysfunction. In summary, our findings demonstrate for the first time that S100A9 plays an important pro-inflammatory role in sepsis-mediated ALI by regulating AKT-AMPK-dependent mitochondrial energy metabolism and highlights that targeting S100A9 may be a promising new approach for the prevention and treatment of sepsis-related liver injury.