Transcriptomics reveals immune-metabolism disorder in acute-on-chronic liver failure in rats

Abstract

Acute-on-chronic liver failure (ACLF) is clinical syndrome with high mortality rate. This study aimed to perform detailed transcriptomic analysis in liver cirrhosis–based ACLF rats to elucidate ACLF pathogenesis. ACLF was induced by combined porcine serum with D-galactosamine and lipopolysaccharide. Gene expression profile of liver tissues from ACLF rats was generated by transcriptome sequencing to reveal the molecular mechanism. ACLF rats successfully developed with typical characteristics. Total of 2,354/3,576 differentially expressed genes were identified when ACLF was compared to liver cirrhosis and normal control, separately. The functional synergy analysis revealed prominent immune dysregulation at ACLF stage, whereas metabolic disruption was significantly down-regulated. Relative proportions of innate immune–related cells showed significant elevation of monocytes and macrophages, whereas adaptive immune–related cells were reduced. The seven differentially expressed genes underlying the ACLF molecular mechanisms were externally validated, among them THBS1, IL-10, and NR4A3 expressions were confirmed in rats, patient transcriptomics, and liver biopsies, verifying their potential value in the ACLF pathogenesis. This study indicates immune-metabolism disorder in ACLF rats, which may provide clinicians new targets for improving intervention strategies.

Systemic inflammatory regulators and risk of acute-on-chronic liver failure: A bidirectional mendelian-randomization study

“…The immunological defects in ACLF patients are similar to those in sepsis patients ( Wan et al, 2013 ). Numerous studies have shown that immune cell fractions vary significantly during ACLF development ( Hassan et al, 2022 ). The inflammatory cytokine pathways (mediators) will be activated and lead to tissue injury.…”

Prospect of Animal Models for Acute-on-chronic Liver Failure: A Mini-review

“…45 Representatives of CCl 4 -dependent models are summarized in Table 1. [28][29][30]32,[45][46][47][48][49][50][51][52][53][54][55][56]…”

“…Furthermore, validations of the underlying molecular pathogenesis in our generated stable rat model and ACLF patients confirmed that immune-metabolism disorder is indispensable in ACLF pathogenesis. 46 …”

Human liver tissue transcriptomics revealed immunometabolic disturbances and related biomarkers in hepatitis B virus-related acute-on-chronic liver failure

“…New strategies for disease diagnosis and treatment can be developed by decoding genome structure and function, rebuilding gene interaction networks and identifying new biomarkers ( Jiang et al, 2015 ). Previous animal studies based on transcriptional profiling revealed that the progression of liver failure was related to the immune response ( Zhang et al, 2018 ; Hassan et al, 2022 ). Furthermore, transcriptomic studies of human peripheral blood mononuclear cells (PBMCs) showed that immunometabolic disorders constitute the core axis of ACLF development ( Li et al, 2022 ).…”