逆转正去氧胆酸在肝脏的蓄积凸显了胆色素对小鼠酒精相关肝病的有益作用。

IF 5.6 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Hepatology Communications Pub Date : 2024-07-31 eCollection Date: 2024-08-01 DOI:10.1097/HC9.0000000000000507
Wei Guo, Wei Zhong, Liqing He, Xiaoyuan Wei, Liuyi Hao, Haibo Dong, Ruichao Yue, Xinguo Sun, Xinmin Yin, Jiangchao Zhao, Xiang Zhang, Zhanxiang Zhou
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引用次数: 0

摘要

背景:据报道,酒精相关性肝病会导致胆汁酸(BA)失调。然而,胆汁酸失衡与酒精相关性肝病之间的因果关系仍不清楚。本研究旨在确定纠正胆汁酸紊乱是否能预防酒精相关性肝病,并阐明其潜在机制:方法:给喂食酒精的 C57BL/6J 小鼠注射 BA 螯合剂胆色素(CTM)8 周,以评估其保护作用并探索潜在的 BA 靶点。通过进一步操纵解毒酶细胞色素 p450 3A11,在肝细胞中检验了已确定的 BA 代谢物与细胞损伤之间的因果关系。在小鼠体内进行的一项急性研究进一步验证了 BA 代谢物的毒性:结果:我们发现 CTM 能有效逆转肝脏 BA 积累,从而逆转酒精诱导的肝脏炎症、细胞死亡、内质网应激和自噬功能障碍。具体来说,疏水性 BA 代谢物去甲氧胆酸(NorDCA)被确定为主要由酒精上调,而 CTM 则会降低其浓度。肝脏细胞色素 p450 3A11 的表达与 NorDCA 的水平平行,酒精会上调,而 CTM 会降低。此外,CTM 还能逆转酒精诱导的肠道屏障破坏和内毒素转运。从机理上讲,NorDCA 与导致内质网应激、抑制自噬通量和诱导细胞损伤有关,而细胞色素 p450 3A11 的过表达可减轻这些有害影响。小鼠急性服用 NorDCA 会显著诱发肝脏炎症和损伤,同时破坏肠道屏障的完整性,导致随后的内毒素血症:我们的研究表明,CTM 治疗可有效逆转酒精诱导的小鼠肝损伤。BA螯合剂的有益作用包括降低有毒的NorDCA水平。NorDCA不仅会加重肝脏内质网应激和抑制自噬,还会介导小鼠肠道屏障破坏和病原体相关分子模式的系统转运。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Reversal of hepatic accumulation of nordeoxycholic acid underlines the beneficial effects of cholestyramine on alcohol-associated liver disease in mice.

Background: Dysregulation of bile acids (BAs) has been reported in alcohol-associated liver disease. However, the causal relationship between BA dyshomeostasis and alcohol-associated liver disease remains unclear. The study aimed to determine whether correcting BA perturbation protects against alcohol-associated liver disease and elucidate the underlying mechanism.

Methods: BA sequestrant cholestyramine (CTM) was administered to C57BL/6J mice fed alcohol for 8 weeks to assess its protective effect and explore potential BA targets. The causal relationship between identified BA metabolite and cellular damage was examined in hepatocytes, with further manipulation of the detoxifying enzyme cytochrome p450 3A11. The toxicity of the BA metabolite was further validated in mice in an acute study.

Results: We found that CTM effectively reversed hepatic BA accumulation, leading to a reversal of alcohol-induced hepatic inflammation, cell death, endoplasmic reticulum stress, and autophagy dysfunction. Specifically, nordeoxycholic acid (NorDCA), a hydrophobic BA metabolite, was identified as predominantly upregulated by alcohol and reduced by CTM. Hepatic cytochrome p450 3A11 expression was in parallel with NorDCA levels, being upregulated by alcohol and reduced by CTM. Moreover, CTM reversed alcohol-induced gut barrier disruption and endotoxin translocation. Mechanistically, NorDCA was implicated in causing endoplasmic reticulum stress, suppressing autophagy flux, and inducing cell injury, and such deleterious effects could be mitigated by cytochrome p450 3A11 overexpression. Acute NorDCA administration in mice significantly induced hepatic inflammation and injury along with disrupting gut barrier integrity, leading to subsequent endotoxemia.

Conclusions: Our study demonstrated that CTM treatment effectively reversed alcohol-induced liver injury in mice. The beneficial effects of BA sequestrant involve lowering toxic NorDCA levels. NorDCA not only worsens hepatic endoplasmic reticulum stress and inhibits autophagy but also mediates gut barrier disruption and systemic translocation of pathogen-associated molecular patterns in mice.

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来源期刊
Hepatology Communications
Hepatology Communications GASTROENTEROLOGY & HEPATOLOGY-
CiteScore
8.00
自引率
2.00%
发文量
248
审稿时长
8 weeks
期刊介绍: Hepatology Communications is a peer-reviewed, online-only, open access journal for fast dissemination of high quality basic, translational, and clinical research in hepatology. Hepatology Communications maintains high standard and rigorous peer review. Because of its open access nature, authors retain the copyright to their works, all articles are immediately available and free to read and share, and it is fully compliant with funder and institutional mandates. The journal is committed to fast publication and author satisfaction. ​
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