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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11150%2F23%3A10471829" target="_blank" >RIV/00216208:11150/23:10471829 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216208:11160/23:10471829 RIV/00179906:_____/23:10471829

Výsledek na webu

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=sfW4dwIXDq" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=sfW4dwIXDq</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1093/toxsci/kfad088" target="_blank" >10.1093/toxsci/kfad088</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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 beta-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 alpha-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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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 beta-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 alpha-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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2023

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Toxicological Sciences

ISSN

1096-6080

e-ISSN

1096-0929

Svazek periodika

196

Číslo periodika v rámci svazku

2

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

18

Strana od-do

200-217

Kód UT WoS článku

001064223100001

EID výsledku v databázi Scopus

2-s2.0-85177845341