Carvedilol is a widely used beta-adrenoreceptor antagonist for multiple cardiovascular indications; however, it may induce cholestasis in patients, but the mechanism for this effect is unclear. Carvedilol also prevents the development of various forms of experimental liver injury, but its effect on nonalcoholic steatohepatitis (NASH) is largely unknown. In this study, we determined the effect of carvedilol (10 mg/kg/day p.o.) on bile formation and bile acid (BA) turnover in male C57BL/6 mice consuming either a chow diet or a western-type NASH-inducing diet. BAs were profiled by liquid chromatography-mass spectrometry and BA-related enzymes, transporters, and regulators were evaluated by western blot analysis and qRT-PCR. In chow diet-fed mice, carvedilol increased plasma concentrations of BAs resulting from reduced BA uptake to hepatocytes via Ntcp transporter downregulation. Inhibition of the β-adrenoreceptor-cAMP-Epac1-Ntcp pathway by carvedilol may be the post-transcriptional mechanism underlying this effect. In contrast, carvedilol did not worsen the deterioration of BA homeostasis accompanying NASH; however, it shifted the spectra of BAs toward more hydrophilic and less toxic α-muricholic and hyocholic acids. This positive effect of carvedilol was associated with a significant attenuation of liver steatosis, inflammation, and fibrosis in NASH mice. In conclusion, our results indicate that carvedilol may increase BAs in plasma by modifying their liver transport. In addition, carvedilol provided significant hepatoprotection in a NASH murine model without worsening BA accumulation. These data suggest beneficial effects of carvedilol in patients at high risk for developing NASH.

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

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

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

Department of Pathology Faculty of Medicine in Hradec Kralove Charles University Hradec Kralove Czech Republic

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

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

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

Division of Gastroenterology and Hepatology Mayo Clinic Rochester Minnesota USA

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

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