Apolipoprotein A-1 protected hepatic ischaemia-reperfusion injury through suppressing macrophage pyroptosis via TLR4-NF-κB pathway.

Abstract

BACKGROUND AND AIMS:

Apolipoprotein A-1 (ApoA-1), the major apolipoprotein of high-density lipoprotein, plays anti-atherogenic role in cardiovascular diseases and exerts anti-inflammation effect in various inflammatory and infectious diseases. However, the role and mechanism of ApoA-1 in hepatic ischaemia-reperfusion (I/R) injury is unknown.

METHODS:

In this study, we measured ApoA-1 expression in human liver grafts after transplantation. Mice partial hepatic I/R injury model was made in ApoA-1 knockout mice, ApoA-1 mimetic peptide D-4F treatment mice and corresponding control mice to examine the effect of ApoA-1 on liver damage, inflammation response and cell death. Primary hepatocytes and macrophages were isolated for in vitro study.

RESULTS:

The results showed that ApoA-1 expression was down-regulated in human liver grafts after transplantation and mice livers subjected to hepatic I/R injury. ApoA-1 deficiency aggravated liver damage and inflammation response induced by hepatic I/R injury. Interestingly, we found that ApoA-1 deficiency increased pyroptosis instead of apoptosis during acute phase of hepatic I/R injury, which mainly occurred in macrophages rather than hepatocytes. The inhibition of pyroptosis compensated for the adverse impact of ApoA-1 deficiency. Furthermore, the up-regulated pyroptosis process was testified to be mediated by ApoA-1 through TLR4-NF-κB pathway and TLR4 inhibition significantly improved hepatic I/R injury. In addition, we confirmed that D-4F ameliorated hepatic I/R injury.

CONCLUSIONS:

Our study has identified the protective role of ApoA-1 in hepatic I/R injury through inhibiting pyroptosis in macrophages via TLR4-NF-κB pathway. The effect of ApoA-1 may provide a novel therapeutic approach for hepatic I/R injury.

• Authors: Rui-Xiang Chen, Wang-Jie Jiang, Shuo-Chen Liu, Zi-Yi Wang, Zhi-Bo Wang, Tao Zhou, Yan-An-Lan Chen, Ji-Fei Wang, Jiang Chang, Yi-Rui Wang, Yao-Dong Zhang, Xue-Hao Wang, Xiang-Cheng Li, Chang-Xian Li
• Journal: Liver international : official journal of the International Association for the Study of the Liver (Liver Int) Vol. 43 Issue 1 Pg. 234-248 (01 2023) ISSN: 1478-3231 [Electronic] United States
• PMID: 36203339 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Chemical References

• NF-kappa B
• Apolipoprotein A-I
• Toll-Like Receptor 4
• TLR4 protein, human
• Tlr4 protein, mouse

Topics

• Humans
• Mice
• Animals
• NF-kappa B (metabolism)
• Apolipoprotein A-I (pharmacology, metabolism, therapeutic use)
• Pyroptosis
• Toll-Like Receptor 4
• Signal Transduction
• Liver (metabolism)
• Liver Diseases (metabolism)
• Reperfusion Injury (prevention & control, metabolism)
• Macrophages (metabolism)