Sepsis related ACLF mouse model
Background and aims: Acute-on-chronic liver failure (ACLF) is an acute liver and multisystem failure in patients with previously stable cirrhosis.  A common cause of ACLF is sepsis secondary to bacterial infection.  Sepsis-associated ACLF involves a loss of differentiated liver function in the absence of direct liver injury, and its mechanism is unknown. We aimed to study the mechanism of sepsis associated ACLF using a novel mouse model.  Approach and Results: Sepsis-associated ACLF was induced by cecal ligation and puncture procedure (CLP) in mice treated with thioacetamide (TAA). The combination of TAA and CLP resulted in a significant decrease in liver synthetic function and high mortality. These changes were associated with reduced metabolic gene expression and increased C/EBPß transcriptional activity.  We found that C/EBPß binding to its target gene promoters was increased. In humans C/EBPß chromatin binding was similarly increased in ACLF group compared to control cirrhosis. Hepatocyte specific Cebpb knockout mice had reduced mortality and increased gene expression of hepatocyte differentiation markers in TAA/CLP mice, suggesting that C/EBPß promotes liver failure in these mice. C/EBPß activation was associated with endothelial dysfunction, characterized by reduced Angiopoietin-1/Angiopoietin-2 ratio and increased endothelial production of HGF. Angiopoietin-1 supplementation or Hgf knockdown reduced hepatocyte C/EBPß accumulation, restored liver function, and reduced mortality, suggesting that endothelial dysfunction induced by sepsis drives acute-on-chronic liver failure via HGF-C/EBPß pathway.  Conclusion: The transcription factor C/EBPß is activated in both mouse and human ACLF and is a potential therapeutic target to prevent liver failure in patients with sepsis and cirrhosis. Overall design: Whole liver mRNA analysis in mice treated with TAA or water as a control and subjected to CLP or sham surgeries