Bile acids (BA) play a significant role in the pathophysiology of nonalcoholic steatohepatitis (NASH). The present study evaluates the modulation of bile acid metabolomics by atorvastatin, a cholesterol-lowering agent commonly used to treat cardiovascular complications accompanying NASH. NASH was induced in mice by 24 weeks of consuming a high-saturated fat, high-fructose, and high-cholesterol diet (F), with atorvastatin administered orally (20 mg/kg/day) during the last three weeks. Biochemical and histological analyses confirmed the effectiveness of the F diet in inducing NASH. Untreated NASH animals had significantly reduced biliary secretion of BA and increased fecal excretion of BA via decreased apical sodium-dependent bile salt transporter (Asbt)-mediated reabsorption. Atorvastatin decreased liver steatosis and inflammation in NASH animals consistently with a reduction in crucial lipogenic enzyme stearoyl-coenzyme A (CoA) desaturase-1 and nuclear factor kappa light chain enhancer of activated B-cell pro-inflammatory signaling, respectively. In this group, atorvastatin also uniformly enhanced plasma concentration, biliary secretion and fecal excretion of the secondary BA, deoxycholic acid (DCA). However, in the chow diet-fed animals, atorvastatin decreased plasma concentrations of BA, and reduced BA biliary secretions. These changes stemmed primarily from the increased fecal excretion of BA resulting from the reduced Asbt-mediated BA reabsorption in the ileum and suppression of synthesis in the liver. In conclusion, our results reveal that atorvastatin significantly modulates BA metabolomics by altering their intestinal processing and liver synthesis in control and NASH mice.

Department of Biological and Medical Sciences Faculty of Pharmacy in Hradec Kralove Charles University 500 03 Hradec Kralove Czech Republic

Department of Histology and Embryology Faculty of Medicine in Hradec Kralove Hradec Kralove Charles University 500 03 Hradec Kralove Czech Republic

Department of Medical Biochemistry Faculty of Medicine in Hradec Kralove Hradec Kralove Charles University 500 03 Hradec Kralove Czech Republic

Department of Pharmacology and Toxicology Faculty of Pharmacy in Hradec Kralove Charles University 500 03 Hradec Kralove Czech Republic

Department of Pharmacology Faculty of Medicine in Hradec Kralove Hradec Kralove Charles University Simkova 870 500 03 Hradec Kralove Czech Republic

Institute of Clinical Biochemistry and Diagnostics University Hospital Hradec Kralove 500 03 Hradec Kralove Czech Republic

The Fingerland Department of Pathology Faculty of Medicine in Hradec Kralove Charles University Hradec Kralove 500 03 Hradec Kralove Czech Republic

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Carvedilol impairs bile acid homeostasis in mice: implication for nonalcoholic steatohepatitis