Sepsis-induced endothelial dysfunction drives acute-on-chronic liver failure through Angiopoietin-2-HGF-C/EBPβ pathway

Abstract

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 CCAAT enhancer binding protein beta (C/EBPβ) transcriptional activity. We found that C/EBPβ binding to its target gene promoters was increased. In humans, C/EBPβ chromatin binding was similarly increased in the ACLF group compared with 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/EBPβ promotes liver failure in these mice. C/EBPβ 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/EBPβ accumulation, restored liver function, and reduced mortality, suggesting that endothelial dysfunction induced by sepsis drives ACLF through HGF-C/EBPβ pathway. Conclusions: The transcription factor C/EBPβ is activated in both mouse and human ACLF and is a potential therapeutic target to prevent liver failure in patients with sepsis and cirrhosis.

Comprehensive analysis of senescence-associated genes in sepsis based on bulk and single-cell sequencing data

“…A high level of HGF is firmly associated with poor outcomes in sepsis patients ( Peng et al, 2021 ). Elias et al (2023) discovered that endothelial dysfunction resulted from sepsis stimulates the production of HGF, which activates C/EBP in liver cells and ultimately causes liver failure or acute-on-chronic liver failure. Upregulated C5a expression in the body exacerbates the progression of sepsis.…”

Targeting cathepsin C ameliorates murine acetaminophen-induced liver injury

“…Of note, VEGF signaling supports repair in murine APAP-induced ALI, particularly in later phases of intoxication 63 , 64 . Angpt2 has been described as surrogate of disease severity in clinical acute liver failure 65 and its relative upregulation (versus Angpt1) in murine acute-on-chronic-liver failure mediates hepatocyte dysfunction and disease via CCAAT/enhancer binding protein-β 50 . Interestingly, Angpt2 can also support production of anti-proliferative transforming growth factor-β1 by LSEC which was demonstrated in murine partial hepatectomy 66 .…”

“…Thereby, we identified three genes previously associated with ALI/acute liver failure that were significantly downregulated in at least three out of the four protocols tested and showed a discernable tendency towards inhibition in a fourth protocol. Those were cxcl2 [17,22] (Figure 4B-E), mmp9 [49] (Figure 4F-I), and angpt2 [50] (Figure 4J-M).…”

Focus on the cGAS-STING Signaling Pathway in Sepsis and Its Inflammatory Regulatory Effects

“… 85 During sepsis, the body releases numerous inflammatory mediators, including cytokines, which can directly or indirectly damage liver cells, leading to impaired liver function. 86 Recent studies suggest that in sepsis-related acute liver injury, STING signaling pathway activation is linked to an intensified inflammatory response and liver injury development. STING activation enhances IFN-I and inflammatory cytokine production, activating the liver’s innate immune cells.…”