3β-Isoobeticholic acid efficiently activates the farnesoid X receptor (FXR) due to its epimerization to 3α-epimer by hepatic metabolism
Language English Country England, Great Britain Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
32505574
DOI
10.1016/j.jsbmb.2020.105702
PII: S0960-0760(20)30227-2
Knihovny.cz E-resources
- Keywords
- Bile acids, Gene regulation, Metabolism, Nuclear receptors, Pharmacokinetics,
- MeSH
- Cell Line MeSH
- Chlorocebus aethiops MeSH
- Isomerism MeSH
- Liver metabolism MeSH
- Chenodeoxycholic Acid analogs & derivatives pharmacology MeSH
- Humans MeSH
- Mice, Inbred C57BL MeSH
- Receptors, Cytoplasmic and Nuclear metabolism MeSH
- Receptors, G-Protein-Coupled genetics metabolism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- farnesoid X-activated receptor MeSH Browser
- GPBAR1 protein, human MeSH Browser
- Chenodeoxycholic Acid MeSH
- Receptors, Cytoplasmic and Nuclear MeSH
- Receptors, G-Protein-Coupled MeSH
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 3β-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 3βhydroxy epimer and its pharmacokinetics in mice were studied using LC-MS. We found that only the 3β-hydroxy epimer of OCA (3β-isoOCA) possesses significant activity to FXR in hepatic cells and mice. However, in a cell-free assay, 3β-isoOCA had about 9-times lower affinity to FXR than did OCA. We observed that 3β-isoOCA readily epimerizes to OCA in hepatocytes and murine liver. This conversion was significantly inhibited by the hydroxy-Δ5-steroid dehydrogenase inhibitor trilostane. In addition, we found that 3,7-dehydroobeticholic acid is a potent GPBAR1 agonist. We conclude that 3β-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.
References provided by Crossref.org
Carvedilol impairs bile acid homeostasis in mice: implication for nonalcoholic steatohepatitis
