1. Characterization of a Structural Leoligin Analog as Farnesoid X Receptor Agonist and Modulator of Cholesterol Transport#.
- Author
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Ladurner, Angela, Linder, Thomas, Wang, Limei, Hiebl, Verena, Schuster, Daniela, Schnürch, Michael, Mihovilovic, Marko D., Atanasov, Atanas G., and Dirsch, Verena M.
- Subjects
CHOLESTEROL metabolism ,CARRIER proteins ,CELL receptors ,GENE expression ,MACROPHAGES ,MEDICINAL plants ,METABOLITES ,MOLECULAR structure ,PLANT extracts ,PEROXISOME proliferator-activated receptors - Abstract
The ligand-activated farnesoid X receptor is an emerging therapeutic target for the development of drugs against metabolic syndrome-related diseases. In this context, selective bile acid receptor modulators represent a novel concept for drug development. Selective bile acid receptor modulators act in a target gene- or tissue-specific way and are therefore considered less likely to elicit unwanted side effects. Based on leoligin, a lignan-type secondary plant metabolite from the alpine plant Leontopodium nivale ssp. alpinum , 168 synthesized structural analogs were screened in a farnesoid X receptor in silico pharmacophore-model. Fifty-six virtual hits were generated. These hits were tested in a cell-based farnesoid X receptor transactivation assay and yielded 7 farnesoid X receptor-activating compounds. The most active one being LT-141A, with an EC
50 of 6 µM and an Emax of 4.1-fold. This analog did not activate the G protein-coupled bile acid receptor, TGR5, and the metabolic nuclear receptors retinoid X receptor α , liver X receptors α / β , and peroxisome proliferator-activated receptors β / γ. Investigation of different farnesoid X receptor target genes characterized LT-141A as selective bile acid receptor modulators. Functional studies revealed that LT-141A increased cholesterol efflux from THP-1-derived macrophages via enhanced ATP-binding cassette transporter 1 expression. Moreover, cholesterol uptake in differentiated Caco-2 cells was significantly decreased upon LT-141A treatment. In conclusion, the leoligin analog LT-141A selectively activates the nuclear receptor farnesoid X receptor and has an influence on cholesterol transport in 2 model systems. [ABSTRACT FROM AUTHOR]- Published
- 2020
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