FXR deficiency alters bile acid pool composition and exacerbates chronic alcohol induced liver injury

Digestive and Liver Disease : Official Journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver
B KongGrace L Guo

Abstract

Recent studies have investigated the roles of FXR deficiency in the pathogenesis of alcoholic liver disease (ALD). However, the underlying molecular mechanisms remain unclear. In this study, FXR knockout (FXR-/-) and wild-type (WT) mice were subjected to chronic-plus-binge alcohol feeding to study the effect of FXR deficiency on ALD development. The degree of liver injury was greater in FXR-/- mice compared to WT mice. Ethanol feeding enhanced hepatic steatosis in FXR-/- mice, accompanied by decreased mRNA levels of Pparα and Srebp-1c. The expression of Lcn2 was increased by ethanol treatment, despite unchanged expression of pro-inflammatory cytokines Tnfα, Il6 and Il-1β. Furthermore, ethanol treatment altered bile acid (BA) homeostasis to a greater extent in FXR-/- mice, as well as serum and hepatic BA pool composition. The mRNA levels of hepatic Cyp7a1 and Shp, as well as intestinal Fgf15, were decreased in WT mice with ethanol feeding, which were further reduced in FXR-/- mice. Levels of both primary and secondary BAs were markedly elevated in FXR-/- mice, which were further increased after ethanol treatment. Moreover, hepatic MAPK signaling pathways were disturbed presumably by increased hepatic BA levels. In summary, FXR d...Continue Reading

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Citations

May 15, 2020·Laboratory Investigation; a Journal of Technical Methods and Pathology·Mingxing HuangGrace L Guo
Sep 11, 2019·Current Opinion in Clinical Nutrition and Metabolic Care·Heli XuJudith Storch
Mar 8, 2020·Liver International : Official Journal of the International Association for the Study of the Liver·Grégory MerlenThierry Tordjmann
Feb 20, 2021·JHEP Reports : Innovation in Hepatology·Valeska Bidault-JourdainneThierry Tordjmann
Apr 18, 2021·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Chunlin LiGuang Ji
May 7, 2021·Evidence-based Complementary and Alternative Medicine : ECAM·Zhe WangYou-Hua Xu
Jul 26, 2021·Phytomedicine : International Journal of Phytotherapy and Phytopharmacology·Lina KongQiang Meng
Jan 30, 2020·Acta Pharmaceutica Sinica. B·Christina Ferrucci-Da SilvaGrace L Guo
Dec 14, 2021·Cellular and Molecular Gastroenterology and Hepatology·Mingjie FanWendong Huang

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