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

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

  • J Steroid Biochem Mol Biol. 2020 Sep;202:105702. doi: 10.1016/j.jsbmb.2020.105702.
Alzbeta Stefela 1,  Miroslav Kaspar 2,  Martin Drastik 3,  Ondrej Holas 4,  Milos Hroch 5,  Tomas Smutny 1,  Josef Skoda 1,  Miriama Hutníková 1,  Amit V Pandey 6,  Stanislav Micuda 7,  Eva Kudova 8,  Petr Pavek 9
Affiliations

Affiliations

  • 1 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Heyrovskeho 1203, Hradec Kralove, 500 05, Czech Republic.
  • 2 Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo Nam. 2, Prague 6 - Dejvice, 166 10, Czech Republic; Faculty of Sciences, Charles University in Prague, Albertov 6, Prague 2, 128 43, Czech Republic.
  • 3 Department of Physical Chemistry, Faculty of Pharmacy, Charles University, Heyrovskeho 1203, Hradec Kralove, 500 05, Czech Republic.
  • 4 Department of Pharmaceutical Technology, Faculty of Pharmacy, Charles University, Heyrovskeho 1203, Hradec Kralove, 500 05, Czech Republic.
  • 5 Department of Medical Biochemistry, Faculty of Medicine in Hradec Kralove, Charles University, Simkova 870/13, Hradec Kralove, 500 03, Czech Republic.
  • 6 Pediatric Endocrinology, University Children's Hospital, Department of Biomedical Research, University of Bern, Bern, Switzerland.
  • 7 Department of Pharmacology, Faculty of Medicine in Hradec Kralove, Charles University, Simkova 870/13, Hradec Kralove, 500 03, Czech Republic.
  • 8 Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo Nam. 2, Prague 6 - Dejvice, 166 10, Czech Republic.
  • 9 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Heyrovskeho 1203, Hradec Kralove, 500 05, Czech Republic. Electronic address: pavek@faf.cuni.cz.
PMID: 32505574 DOI: 10.1016/j.jsbmb.2020.105702
Abstract

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.

Keywords

Bile acids; Gene regulation; Metabolism; Nuclear receptors; Pharmacokinetics.

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