Center for Translational Biomedical Research.
Department of Nutrition, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, USA.
Hepatol Commun. 2024 Jul 31;8(8). doi: 10.1097/HC9.0000000000000507. eCollection 2024 Aug 1.
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.
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.
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.
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.
已有研究报道，在酒精相关性肝病中存在胆汁酸（BAs）的失调。然而，BA 代谢紊乱与酒精相关性肝病之间的因果关系尚不清楚。本研究旨在确定纠正 BA 扰动是否能预防酒精相关性肝病，并阐明其潜在机制。
用胆盐螯合剂考来烯胺（CTM）对连续 8 周摄入酒精的 C57BL/6J 小鼠进行处理，以评估其保护作用，并探讨潜在的 BA 靶点。在肝细胞中进一步研究鉴定出的 BA 代谢物与细胞损伤之间的因果关系，并进一步操纵解毒酶细胞色素 P450 3A11。在急性研究中进一步验证了 BA 代谢物的毒性。
我们发现 CTM 可有效逆转肝脏 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。具体而言，发现去氧胆酸（NorDCA）是一种主要由酒精上调且被 CTM 下调的疏水性 BA 代谢物。肝细胞色素 P450 3A11 的表达与 NorDCA 水平平行，被酒精上调，被 CTM 下调。此外，CTM 还可逆转酒精诱导的肠道屏障破坏和内毒素易位。在机制上，NorDCA 被认为可导致内质网应激、抑制自噬流并诱导细胞损伤，而过表达细胞色素 P450 3A11 可减轻这些有害作用。在小鼠中急性给予 NorDCA 可显著诱导肝脏炎症和损伤，同时破坏肠道屏障完整性，导致随后的内毒素血症。
本研究表明 CTM 治疗可有效逆转小鼠的酒精性肝损伤。BA 螯合剂的有益作用涉及降低毒性 NorDCA 水平。NorDCA 不仅加重肝脏内质网应激和抑制自噬，而且还介导肠道屏障破坏和全身病原体相关分子模式的易位。
