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

> **NIH NIH R21** · UNIVERSITY OF KANSAS MEDICAL CENTER · 2024 · $232,499

## Abstract

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 def...

## Key facts

- **NIH application ID:** 10865721
- **Project number:** 1R21AI178204-01A1
- **Recipient organization:** UNIVERSITY OF KANSAS MEDICAL CENTER
- **Principal Investigator:** Irina Tikhanovich
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $232,499
- **Award type:** 1
- **Project period:** 2024-07-08 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10865721

## Citation

> US National Institutes of Health, RePORTER application 10865721, The role of C/EBPß in sepsis associated acute-on-chronic liver failure (1R21AI178204-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10865721. Licensed CC0.

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