Cholestatic liver diseases are characterized by intrahepatic accumulation of bile acids (BAs), exacerbating liver inflammation, and fibrosis. Dimethyl fumarate (DMF) is a clinically approved antiinflammatory drug that demonstrated protective effects in several experimental models of liver injury. Still, its effect on BA homeostasis and liver fibrosis has not been thoroughly studied. Herein, we hypothesized that DMF could improve BA homeostasis and mitigate the progression of cholestasis-induced liver fibrosis. The DMF was administered to mice with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced cholestasis for four weeks. The content of individual BAs in the plasma, liver, bile, intestine, and feces was measured using the LC-MS method alongside the analysis of liver phenotype and related executive and regulatory pathways. The DMF slowed down the progression of DDC-induced liver fibrosis by suppressing hepatic stellate cell (HSC) and macrophage activation, and by reducing c-Jun N-terminal kinase (JNK) phosphorylation. Notably, DMF reduced BA cumulation in the plasma and liver of cholestatic mice by increasing BA fecal excretion via their reduced Bacteroidetes phyla-mediated deconjugation in the intestine. In addition, DMF was identified as the antagonist of the mouse FXR receptor in enterocytes. In conclusion, DMF alleviates DDC-induced cholestatic liver injury through pleiotropic action leading to significant anti-inflammatory and antifibrotic activity of the agent. Additionally, DMF mitigates BA retention in the liver and plasma by increasing their fecal excretion in cholestatic mice. These findings suggest that DMF warrants further investigation as a potential therapeutic agent for human chronic fibrosing cholestatic liver disorders.

Department of Biological and Medical Sciences Faculty of Pharmacy in Hradec Kralove Charles University Heyrovskeho 1203 500 05 Hradec Kralove Czech Republic

Department of Histology and Embryology Faculty of Medicine in Hradec Kralove Charles University Simkova 870 50003 Hradec Kralove Czech Republic

Department of Medical Biochemistry Faculty of Medicine in Hradec Kralove Charles University Simkova 870 50003 Hradec Kralove Czech Republic

Department of Pharmacology and Toxicology Faculty of Pharmacy in Hradec Kralove Charles University Heyrovskeho 1203 500 05 Hradec Kralove Czech Republic

Department of Pharmacology Faculty of Medicine in Hradec Kralove Charles University Simkova 870 50003 Hradec Kralove Czech Republic

Department of Physiology Faculty of Medicine in Hradec Kralove Charles University Simkova 870 50003 Hradec Kralove Czech Republic

Department of Toxicology and Military Pharmacy Military Faculty of Medicine University of Defence Trebesska 1575 500 01 Hradec Kralove Czech Republic

Division of Gastroenterology and Hepatology Mayo Clinic Rochester Minnesota USA

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