Pengpeng Yue, Xiaoyan Lv, Hankun Cao, Yongkang Zou, Jian You, Jun Luo, Zhongshan Lu, Hao Chen, Zhongzhong Liu, Zibiao Zhong, Yan Xiong, Xiaoli Fan, Qifa Ye
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引用次数: 0
Abstract
The use of fatty livers in liver transplantation has emerged as a crucial strategy to expand the pool of donor livers; however, fatty livers are more sensitive to ischemia‒reperfusion injury (IRI). Excessive congenital inflammatory responses are crucial in IRI. Hypothermic oxygenated perfusion (HOPE) is a novel organ preservation technique that may improve marginal donor liver quality by reducing the inflammatory response. Tissue factor pathway inhibitor-2 (TFPI2) and CAP-Gly domain-containing linker protein 1 (CLIP1) exhibit modulatory effects on the inflammatory response. However, the underlying mechanisms of HOPE in fatty liver and the effects of TFPI2 and CLIP1 in fatty liver IRI remain unclear. Here, we aimed to explore the impact of HOPE on the inflammatory response in a rat model of fatty liver IRI and the mechanisms of action of TFPI2 and CLIP1. HOPE significantly reduces liver injury, especially the inflammatory response, and alleviates damage to hepatocytes and endothelial cells. Mechanistically, HOPE exerts its effects by inhibiting TFPI2, and CLIP1 can rescue the damaging effects of TFPI2. Moreover, HOPE promoted the ubiquitination and subsequent degradation of Toll/interleukin-1 receptor domain-containing adapter protein (TIRAP) by regulating the binding of R24 of the KD1 domain of TFPI2 with CLIP1, thereby negatively regulating the TLR4/NF-κB-mediated inflammatory response and reducing IRI. Furthermore, TFPI2 expression increased and CLIP1 expression decreased following cold ischemia in human fatty livers. Overall, our results suggest that targeting the inflammatory response by modulating the TFPI2/CLIP1/TIRAP signaling pathway via HOPE represents a potential therapeutic approach to ameliorate IRI during fatty liver transplantation. Liver transplantation is the only effective treatment for end-stage liver disease, but donor organ shortages limit its progress. Researchers found that fatty livers, which make up 15-30% of donations, are more prone to damage during transplantation. In this study, the researchers used a rat model to explore how hypothermic oxygenated perfusion (HOPE) affects fatty liver transplants. HOPE is a technique where the liver is preserved at low temperatures with oxygenated fluid. They divided rats into three groups: sham, cold storage (CS), and HOPE. Results showed that HOPE significantly reduces liver injury, especially the inflammatory response, and alleviates oxidative stress to improve liver function. The researchers concluded that HOPE can protect fatty livers during transplantation by inhibiting inflammation. Future studies could explore HOPE’s potential in human liver transplants. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
期刊介绍:
Experimental & Molecular Medicine (EMM) stands as Korea's pioneering biochemistry journal, established in 1964 and rejuvenated in 1996 as an Open Access, fully peer-reviewed international journal. Dedicated to advancing translational research and showcasing recent breakthroughs in the biomedical realm, EMM invites submissions encompassing genetic, molecular, and cellular studies of human physiology and diseases. Emphasizing the correlation between experimental and translational research and enhanced clinical benefits, the journal actively encourages contributions employing specific molecular tools. Welcoming studies that bridge basic discoveries with clinical relevance, alongside articles demonstrating clear in vivo significance and novelty, Experimental & Molecular Medicine proudly serves as an open-access, online-only repository of cutting-edge medical research.