scholarly journals Introduction of Nonacidic Side Chains on 6-Ethylcholane Scaffolds in the Identification of Potent Bile Acid Receptor Agonists with Improved Pharmacokinetic Properties

Molecules ◽  
2019 ◽  
Vol 24 (6) ◽  
pp. 1043 ◽  
Author(s):  
Claudia Finamore ◽  
Giuliana Baronissi ◽  
Silvia Marchianò ◽  
Francesco Di Leva ◽  
Adriana Carino ◽  
...  
Keyword(s):  
Bile Acid ◽  
Metabolic Disorders ◽  
Farnesoid X Receptor ◽  
Pharmacological Characterization ◽  
Acid Receptor ◽  
Pharmacokinetic Properties ◽  
Docking Calculations ◽  
Bile Acid Receptor ◽  
Receptor Modulators

As a cellular bile acid sensor, farnesoid X receptor (FXR) and the membrane G-coupled receptor (GPBAR1) participate in maintaining bile acid, lipid, and glucose homeostasis. To date, several selective and dual agonists have been developed as promising pharmacological approach to metabolic disorders, with most of them possessing an acidic conjugable function that might compromise their pharmacokinetic distribution. Here, guided by docking calculations, nonacidic 6-ethyl cholane derivatives have been prepared. In vitro pharmacological characterization resulted in the identification of bile acid receptor modulators with improved pharmacokinetic properties.

Characterization of a Structural Leoligin Analog as Farnesoid X Receptor Agonist and Modulator of Cholesterol Transport

Planta Medica ◽  
2020 ◽  
Vol 86 (15) ◽  
pp. 1097-1107
Author(s):  
Angela Ladurner ◽  
Thomas Linder ◽  
Limei Wang ◽  
Verena Hiebl ◽  
Daniela Schuster ◽  
...  
Keyword(s):  
Bile Acid ◽  
Target Genes ◽  
Pharmacophore Model ◽  
Farnesoid X Receptor ◽  
Model Systems ◽  
Cholesterol Transport ◽  
Peroxisome Proliferator ◽  
Acid Receptor ◽  
Bile Acid Receptor ◽  
Receptor Modulators

AbstractThe 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 EC50 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.

Glucose sensing O-GlcNAcylation pathway regulates the nuclear bile acid receptor farnesoid X receptor (FXR)

Hepatology ◽  
2014 ◽  
Vol 59 (5) ◽  
pp. 2022-2033 ◽  
Author(s):  
Wahiba Berrabah ◽  
Pierrette Aumercier ◽  
Céline Gheeraert ◽  
Hélène Dehondt ◽  
Emmanuel Bouchaert ◽  
...  
Keyword(s):  
Bile Acid ◽  
Glucose Sensing ◽  
Farnesoid X Receptor ◽  
Acid Receptor ◽  
Bile Acid Receptor

Neutraceutical Targeting of the Bile Acid Receptor, Farnesoid X Receptor, for Intestinal Disease

2020 ◽  
Vol 34 (S1) ◽  
pp. 1-1
Author(s):  
Ciara M. Fallon ◽  
Omprakash Edupuganti ◽  
Natalia K. Lajczak-McGinley ◽  
Helen Sheridan ◽  
Stephen J. Keely
Keyword(s):  
Bile Acid ◽  
Farnesoid X Receptor ◽  
Intestinal Disease ◽  
Acid Receptor ◽  
Bile Acid Receptor

scholarly journals The nuclear bile acid receptor FXR is activated by PGC-1α in a ligand-dependent manner

2004 ◽  
Vol 382 (3) ◽  
pp. 913-921 ◽  
Author(s):  
Eiko KANAYA ◽  
Takuma SHIRAKI ◽  
Hisato JINGAMI
Keyword(s):  
Bile Acid ◽  
Ligand Binding ◽  
Transcriptional Activation ◽  
Expression System ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Farnesoid X Receptor ◽  
Dependent Manner ◽  
Acid Receptor ◽  
Bile Acid Receptor

The nuclear bile acid receptor FXR (farnesoid X receptor) is one of the key factors that suppress bile acid biosynthesis in the liver. PGC-1α [PPARγ (peroxisome-proliferator-activated receptor γ) co-activator-1α] is known to control energy homoeostasis in adipose tissue, skeletal muscle and liver. We performed cell-based reporter assays using the expression system of a GAL4–FXR chimaera, the ligand-binding domain of FXR fused to the DNA-binding domain of yeast GAL4, to find the co-activators for FXR. We found that the transcriptional activation of a reporter plasmid by a GAL4–FXR chimaera was strongly enhanced by PGC-1α, in a ligand-dependent manner. Transcriptional activation of the SHP (small heterodimer partner) gene by the FXR–RXRα (retinoid X receptor α) heterodimer was also enhanced by PGC-1α in the presence of CDCA (chenodeoxycholic acid). Co-immunoprecipitation and pull-down studies using glutathione S-transferase–PGC-1α fusion proteins revealed that the ligand-binding domain of FXR binds PGC-1α in a ligand-influenced manner both in vivo and in vitro. Furthermore, our studies revealed that SHP represses its own transcription, and the addition of excess amounts of PGC-1α can overcome the inhibitory effect of SHP. These observations indicate that PGC-1α mediates the ligand-dependent activation of FXR and transcription of SHP gene.

scholarly journals Intestine farnesoid X receptor agonist and the gut microbiota activate G‐protein bile acid receptor‐1 signaling to improve metabolism

Hepatology ◽  
2018 ◽  
Vol 68 (4) ◽  
pp. 1574-1588 ◽  
Author(s):  
Preeti Pathak ◽  
Cen Xie ◽  
Robert G. Nichols ◽  
Jessica M. Ferrell ◽  
Shannon Boehme ◽  
...  
Keyword(s):  
Bile Acid ◽  
Gut Microbiota ◽  
G Protein ◽  
Receptor Agonist ◽  
Farnesoid X Receptor ◽  
Acid Receptor ◽  
Bile Acid Receptor
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