3 beta-Isoobeticholic acid efficiently activates the farnesoid X receptor (FXR) due to its epimerization to 3 alpha-epimer by hepatic metabolism

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11150%2F20%3A10417948" target="_blank" >RIV/00216208:11150/20:10417948 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216208:11160/20:10417948 RIV/00216208:11310/20:10417948

Výsledek na webu

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

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.jsbmb.2020.105702" target="_blank" >10.1016/j.jsbmb.2020.105702</a>

Jazyk výsledku

angličtina

Název v původním jazyce

3 beta-Isoobeticholic acid efficiently activates the farnesoid X receptor (FXR) due to its epimerization to 3 alpha-epimer by hepatic metabolism

Popis výsledku v původním jazyce

Bile acids (BAs) are important signaling molecules acting via the farnesoid X nuclear receptor (FXR) and the membrane G protein-coupled bile acid receptor 1 (GPBAR1). Besides deconjugation of BAs, the oxidoreductive enzymes of colonic bacteria and hepatocytes enable the conversion of BAs into their epimers or dehydrogenated forms. Obeticholic acid (OCA) is the first-in-class BA-derived FXR agonist approved for the treatment of primary biliary cholangitis. Herein, a library of OCA derivatives, including 7-keto, 6-ethylidene derivatives and 3 beta-epimers, was synthetized and investigated in terms of interactions with FXR and GPBAR1 in transaction assays and evaluated for FXR target genes expression in human hepatocytes and C57BL/6 mice. The derivatives were further subjected to cell-free analysis employing in silico molecular docking and a TR-FRET assay. The conversion of the 3 beta-hydroxy epimer and its pharmacokinetics in mice were studied using LC-MS. We found that only the 3 beta-hydroxy epimer of OCA (3 beta-isoOCA) possesses significant activity to FXR in hepatic cells and mice. However, in a cell-free assay, 3 beta-isoOCA had about 9-times lower affinity to FXR than did OCA. We observed that 3 beta-isoOCA readily epimerizes to OCA in hepatocytes and murine liver. This conversion was significantly inhibited by the hydroxy-Delta(5)-steroid dehydrogenase inhibitor trilostane. In addition, we found that 3,7-dehydroobeticholic acid is a potent GPBAR1 agonist. We conclude that 3 beta-isoOCA significantly activates FXR due to its epimerization to the more active OCA by hepatic metabolism. Other modifications as well as epimerization on the C3/C7 positions and the introduction of 6-ethylidene in the CDCA scaffold abrogate FXR agonism and alleviate GPBAR1 activation.

Název v anglickém jazyce

3 beta-Isoobeticholic acid efficiently activates the farnesoid X receptor (FXR) due to its epimerization to 3 alpha-epimer by hepatic metabolism

Popis výsledku anglicky

Bile acids (BAs) are important signaling molecules acting via the farnesoid X nuclear receptor (FXR) and the membrane G protein-coupled bile acid receptor 1 (GPBAR1). Besides deconjugation of BAs, the oxidoreductive enzymes of colonic bacteria and hepatocytes enable the conversion of BAs into their epimers or dehydrogenated forms. Obeticholic acid (OCA) is the first-in-class BA-derived FXR agonist approved for the treatment of primary biliary cholangitis. Herein, a library of OCA derivatives, including 7-keto, 6-ethylidene derivatives and 3 beta-epimers, was synthetized and investigated in terms of interactions with FXR and GPBAR1 in transaction assays and evaluated for FXR target genes expression in human hepatocytes and C57BL/6 mice. The derivatives were further subjected to cell-free analysis employing in silico molecular docking and a TR-FRET assay. The conversion of the 3 beta-hydroxy epimer and its pharmacokinetics in mice were studied using LC-MS. We found that only the 3 beta-hydroxy epimer of OCA (3 beta-isoOCA) possesses significant activity to FXR in hepatic cells and mice. However, in a cell-free assay, 3 beta-isoOCA had about 9-times lower affinity to FXR than did OCA. We observed that 3 beta-isoOCA readily epimerizes to OCA in hepatocytes and murine liver. This conversion was significantly inhibited by the hydroxy-Delta(5)-steroid dehydrogenase inhibitor trilostane. In addition, we found that 3,7-dehydroobeticholic acid is a potent GPBAR1 agonist. We conclude that 3 beta-isoOCA significantly activates FXR due to its epimerization to the more active OCA by hepatic metabolism. Other modifications as well as epimerization on the C3/C7 positions and the introduction of 6-ethylidene in the CDCA scaffold abrogate FXR agonism and alleviate GPBAR1 activation.

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

2020

Kód důvěrnosti údajů

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

Název periodika

Journal of Steroid Biochemistry and Molecular Biology

ISSN

0960-0760

e-ISSN

—

Svazek periodika

202

Číslo periodika v rámci svazku

September

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

13

Strana od-do

105702

Kód UT WoS článku

000568821700007

EID výsledku v databázi Scopus

2-s2.0-85086573279