Cholestatic liver diseases are characterized by intrahepatic accumulation of bile acids (BAs), exacerbating liver inflammation, and fibrosis. Dimethyl fumarate (DMF) is a clinically approved anti-inflammatory 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 4 wk. 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 and macrophage activation and by reducing c-Jun N-terminal kinase 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 farnesoid X 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. In addition, 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.NEW & NOTEWORTHY Chronic cholestatic cholangiopathies present a therapeutic challenge due to their complex pathophysiology, where the accumulation of bile acids plays a crucial role. In this study, we found that dimethyl fumarate attenuated cholestatic liver damage in a murine model through its significant anti-inflammatory and antifibrotic activity supported by reduced bile acid accumulation in the plasma and liver via their increased fecal excretion.

• MeSH
• Cholestasis * drug therapy   metabolism   chemically induced   MeSH
• Dimethyl Fumarate * pharmacology   therapeutic use   MeSH
• Liver Cirrhosis * metabolism   drug therapy   pathology   etiology   MeSH
• Hepatic Stellate Cells drug effects   metabolism   MeSH
• Liver * metabolism   drug effects   pathology   MeSH
• Disease Models, Animal MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Bile Acids and Salts * metabolism   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH