The role of C/EBPß in sepsis associated acute-on-chronic liver failure

PROJECT SUMMARY Acute-on-chronic liver failure (ACLF) is a clinical syndrome in which there is rapid development of liver and multi- organ system failure in a patient with previously stable cirrhosis. There are two different types of ACLF. In the

first, the precipitating insult directly injures the liver and liver failure is a direct consequence of this injury. In the second, the precipitating event is typically sepsis, and this unexpectedly results in the sudden loss of liver function without massive liver cell death and its mechanism is unknown. There have been very few mechanistic

studies of ACLF to date due to the lack of an appropriate animal model. Recently we developed a mouse model of sepsis related ACLF. We found that sepsis induction in mice with advanced liver fibrosis results in high mortality and a rapid decrease in liver function, associated with a decrease in differentiation markers, such as Alb, and an increase in hepatocyte expression of C/EBPβ

Preliminary data indicate that the key mechanism responsible for loss of liver function is linked to endothelial cell dysregulation mediated by angiopoietin imbalance and C/EBPβ signaling in hepatocytes. Angiopoietin-1 and -2 are key regulators of endothelial cell fate and function, dynamic changes in angiopoietins control both

regenerative response after liver injury and ensuing return to homeostatic state. Increased ANG-2/ANG-1 ratio is a well-known feature of ACLF. Preliminary experiments indicated that angiopoietins profoundly altered endothelial cell-hepatocyte crosstalk. While ANG-1 promoted hepatocyte albumin production, ANG-2

suppressed hepatocyte differentiation while increasing C/EBPβ expression and cell proliferation. However, the mediators of this endothelial cell-hepatocyte crosstalk are not known. C/EBPβ is a transcription factor that regulates the expression of genes involved in the acute phase response, metabolic functions, and cell cycle progression. C/EBPβ is transiently activated during liver regeneration.

However, sustained activation is harmful because it may prevent re-differentiation. Preliminary data indicated that C/EBPβ is activated in ACLF mice and in human ACLF samples. Activated C/EBPβ promoted sustained suppression of metabolic and hepatocyte differentiation genes. Hepatocyte specific Cebpb knockout increased

gene expression of hepatocyte differentiation markers and prevented mortality in ACLF model. Taken together, we hypothesize that endothelial dysfunction mediated by sepsis in the presence of liver fibrosis promotes sustained activation of C/EBPβ in hepatocytes that in turn promotes loss of hepatocyte differentiation

and liver failure in ACLF. We propose to study C/EBPβ-mediated loss of liver function in ACLF using mouse models and human liver transplant explants; and find the link between endothelial dysfunction and C/EBPβ activation. The results of this project will define if C/EBPβ promotes liver failure in ACLF and will set stage for

future studies defining C/EBPβ function and ultimately identifying new therapeutic targets of sepsis ACLF.