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Trimethylamine N-oxide exacerbates acetaminophen-induced liver injury by interfering with macrophage-mediated liver regeneration
Journal of Cellular Physiology ( IF 5.6 ) Pub Date : 2021-08-29 , DOI: 10.1002/jcp.30568
Mingzhu Yan 1, 2 , Chong Zhao 1 , Shangyun Lu 1 , Jinling Cui 1 , Zhenou Sun 1 , Xiaoyi Liu 1 , Shuo Liu 1 , Yazhen Huo 3 , Shutao Yin 1 , Hongbo Hu 1
Affiliation  

Acetaminophen (APAP)-induced acute liver injury (AILI) is the most frequent cause of acute liver failure in developed countries. Trimethylamine N-oxide (TMAO) is a metabolite derived from the gut microbiota and is relatively high in the circulation of the elderly, individuals with diabetes, and heart disease. Herein, we showed that TMAO exacerbates APAP hepatotoxicity. It is possible that delayed liver repair and regeneration that resulted from reduced macrophage accumulation was responsible for this combined hepatotoxicity. Moreover, matrix metalloproteinase 12 (Mmp12), expressed predominantly by macrophages, were reduced by TMAO in vitro and in vivo. This led to the inhibition of macrophage migration and a subsequent decrease in the recruitment of proresolving macrophages to the necrosis area. Furthermore, the administration of recombinant Mmp12 mitigated the enhanced hepatotoxicity in mice cotreated with TMAO and APAP. Overall, this study indicates that TMAO exacerbates APAP-induced hepatotoxicity by hindering macrophage-mediated liver repair, which might stem from the inhibition of Mmp12. These findings imply that liver damage in patients with high levels of circulating TMAO may be more severe in AILI and should exercise caution when treating with NAC.

中文翻译:

三甲胺 N-氧化物通过干扰巨噬细胞介导的肝再生加剧对乙酰氨基酚诱导的肝损伤

对乙酰氨基酚(APAP)引起的急性肝损伤(AILI)是发达国家急性肝衰竭最常见的原因。三甲胺 N-氧化物 (TMAO) 是一种源自肠道微生物群的代谢物,在老年人、糖尿病患者和心脏病患者的循环中含量相对较高。在此,我们发现 TMAO 会加剧 APAP 的肝毒性。巨噬细胞积累减少导致的肝脏修复和再生延迟可能是造成这种联合肝毒性的原因。此外,主要由巨噬细胞表达的基质金属蛋白酶 12 (Mmp12) 在体外和体内被 TMAO 降低。这导致了巨噬细胞迁移的抑制和随后向坏死区域募集促分解巨噬细胞的减少。此外,重组 Mmp12 的施用减轻了用 TMAO 和 APAP 共同治疗的小鼠的肝毒性增强。总体而言,这项研究表明,TMAO 通过阻碍巨噬细胞介导的肝修复来加剧 APAP 诱导的肝毒性,这可能源于对 Mmp12 的抑制。这些发现表明,循环 TMAO 水平高的患者的肝损伤在 AILI 中可能更严重,在使用 NAC 治疗时应谨慎。
更新日期:2021-08-29
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