山奈酚通过靶向肠道 FXR-FGF15 信号抑制肝内胆汁酸合成改善酒精性肝病。
Kaempferol ameliorated alcoholic liver disease through inhibiting hepatic bile acid synthesis by targeting intestinal FXR-FGF15 signaling.
机构信息
College of Basic Medical Science, China Three Gorges University, Yichang, China; Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, College of Medicine and Health Sciences, China Three Gorges University, Yichang, China.
College of Basic Medical Science, China Three Gorges University, Yichang, China.
出版信息
Phytomedicine. 2023 Nov;120:155055. doi: 10.1016/j.phymed.2023.155055. Epub 2023 Sep 5.
BACKGROUND
Alcoholic liver disease (ALD) is characterized by the disturbance of bile acids homeostasis, which further deteriorates ALD. Bile acid metabolism and its related signal molecules have become new therapeutic targets for alcoholic liver disease. This study aimed to investigate the impact of kaempferol (KAE) on ALD and elucidate its underlying mechanisms.
METHODS
C57BL/6 N mice were utilized to establish Binge-on-Chronic alcohol exposure mice model. KAE was administered as an interventional drug to chronic alcohol-fed mice for four weeks to assess its effects on liver damage and bile acid metabolism. And Z-Guggulsterone (Z-Gu), a global FXR inhibitor, was used to investigate the impact of intestinal FXR-FGF15 signal in ALD mice. Additionally, intestinal epithelial cells were exposed to alcohol or specific bile acid to induce the damage of FXR activity in vitro. The dual luciferase activity assay was employed to ascertain the interplay between KAE and FXR activity.
RESULTS
The results indicated that KAE treatment exhibited a significant hepatoprotective effect against chronic alcohol-fed mice. Accompanied by the intestinal FXR activation, the administration of KAE suppressed hepatic bile acid synthesis and promoted intestinal bile acid excretion in chronic ALD mice. And the notable alterations in total bile acid levels and composition were observed in mice after chronic alcohol feeding, which were reversed by KAE supplementation. And more, the protective effects of KAE on ALD mice were deprived by the inhibition of intestinal FXR activation. In vitro experiments demonstrated that KAE effectively activated FXR-FGF15 signaling, mitigated the damage to FXR activity in intestinal epithelial cells caused by alcohol or specific bile acids. Additionally, luciferase activity assays revealed that KAE directly promoted FXR expression, thereby enhancing FXR activity.
CONCLUSION
KAE treatment inhibited hepatic bile acids synthesis, maintained bile acids homeostasis in ALD mice by directly activating intestinal FXR-FGF15 signaling, which effectively alleviated liver injury induced by chronic alcohol consumption.
背景
酒精性肝病（ALD）的特征是胆汁酸稳态紊乱，这进一步恶化了 ALD。胆汁酸代谢及其相关信号分子已成为治疗酒精性肝病的新靶点。本研究旨在探讨山奈酚（KAE）对 ALD 的影响，并阐明其潜在机制。
方法
使用 C57BL/6N 小鼠建立 binge-on-chronic 酒精暴露小鼠模型。用 KAE 作为干预药物给慢性酒精喂养的小鼠给药四周，以评估其对肝损伤和胆汁酸代谢的影响。并用 Z-Guggulsterone（Z-Gu），一种全球 FXR 抑制剂，来研究肠道 FXR-FGF15 信号对 ALD 小鼠的影响。此外，将肠上皮细胞暴露于酒精或特定的胆汁酸中，以在体外诱导 FXR 活性损伤。双荧光素酶活性测定用于确定 KAE 和 FXR 活性之间的相互作用。
结果
结果表明，KAE 治疗对慢性酒精喂养的小鼠具有显著的保肝作用。伴随着肠道 FXR 激活，KAE 抑制了慢性 ALD 小鼠的肝胆汁酸合成，并促进了肠道胆汁酸排泄。在慢性酒精喂养后，小鼠的总胆汁酸水平和组成发生了显著变化，而 KAE 补充则逆转了这些变化。更重要的是，肠道 FXR 激活的抑制剥夺了 KAE 对 ALD 小鼠的保护作用。体外实验表明，KAE 有效激活了 FXR-FGF15 信号通路，减轻了酒精或特定胆汁酸对肠上皮细胞 FXR 活性的损伤。此外，荧光素酶活性测定显示，KAE 直接促进了 FXR 的表达，从而增强了 FXR 的活性。
结论
KAE 治疗通过直接激活肠道 FXR-FGF15 信号抑制肝胆汁酸合成，维持 ALD 小鼠胆汁酸稳态，有效缓解慢性酒精摄入引起的肝损伤。
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