Kaempferol ameliorated alcoholic liver disease through inhibiting hepatic bile acid synthesis by targeting intestinal FXR-FGF15 signaling

Li Xiao; Guangfu Xu; Silong Chen; Yumin He; Fan Peng; Chengfu Yuan

doi:10.1016/j.phymed.2023.155055

Kaempferol ameliorated alcoholic liver disease through inhibiting hepatic bile acid synthesis by targeting intestinal FXR-FGF15 signaling

Phytomedicine. 2023 Nov:120:155055. doi: 10.1016/j.phymed.2023.155055. Epub 2023 Sep 5.

Authors

Li Xiao¹, Guangfu Xu², Silong Chen³, Yumin He³, Fan Peng², Chengfu Yuan⁴

Affiliations

¹ 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.
² College of Basic Medical Science, China Three Gorges University, Yichang, China.
³ 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.
⁴ 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. Electronic address: yuancf46@ctgu.edu.cn.

PMID: 37678053
DOI: 10.1016/j.phymed.2023.155055

Abstract

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.

Keywords: Alcoholic liver disease; Bile acid; Cyp7A1; FXR; Kaempferol.

MeSH terms

Animals
Bile Acids and Salts
Ethanol
Kaempferols* / pharmacology
Liver Diseases, Alcoholic* / drug therapy
Luciferases
Mice
Mice, Inbred C57BL

Substances

Kaempferols
Ethanol
Bile Acids and Salts
Luciferases