scholarly journals Targeting Bile Acid Receptors: Discovery of a Potent and Selective Farnesoid X Receptor Agonist as a New Lead in the Pharmacological Approach to Liver Diseases

2017 ◽  
Vol 8 ◽  
Author(s):  
Carmen Festa ◽  
Simona De Marino ◽  
Adriana Carino ◽  
Valentina Sepe ◽  
Silvia Marchianò ◽  
...  
Keyword(s):  
Bile Acid ◽  
Liver Diseases ◽  
Receptor Agonist ◽  
Farnesoid X Receptor ◽  
Pharmacological Approach ◽  
Bile Acid Receptors

scholarly journals The response of patients with bile acid diarrhoea to the farnesoid X receptor agonist obeticholic acid

2014 ◽  
Vol 41 (1) ◽  
pp. 54-64 ◽  
Author(s):  
J. R. F. Walters ◽  
I. M. Johnston ◽  
J. D. Nolan ◽  
C. Vassie ◽  
M. E. Pruzanski ◽  
...  
Keyword(s):  
Bile Acid ◽  
Receptor Agonist ◽  
Farnesoid X Receptor ◽  
Obeticholic Acid

Disease-Associated Changes in Bile Acid Profiles and Links to Altered Gut Microbiota

2017 ◽  
Vol 35 (3) ◽  
pp. 169-177 ◽  
Author(s):  
Susan A. Joyce ◽  
Cormac G.M. Gahan
Keyword(s):  
Bile Acid ◽  
Gut Microbiota ◽  
Bile Acids ◽  
Farnesoid X Receptor ◽  
Gastrointestinal Microbiota ◽  
Signalling Molecules ◽  
Disease States ◽  
Irritable Bowel ◽  
Bile Acid Profiles ◽  
Bile Acid Receptors

The gastrointestinal microbiota plays a central role in the host metabolism of bile acids through deconjugation and dehydroxylation reactions, which generate unconjugated free bile acids and secondary bile acids respectively. These microbially generated bile acids are particularly potent signalling molecules that interact with host bile acid receptors (including the farnesoid X receptor, vitamin D receptor and TGR5 receptor) to trigger cellular responses that play essential roles in host lipid metabolism, electrolyte transport and immune regulation. Perturbations of microbial populations in the gut can therefore profoundly alter bile acid profiles in the host to impact upon the digestive and signalling properties of bile acids in the human superorganism. A number of recent studies have clearly demonstrated the occurrence of microbial disturbances allied to alterations in host bile acid profiles that occur across a range of disease states. Intestinal diseases including irritable bowel syndrome, inflammatory bowel disease (IBD), short bowel syndrome and Clostridium difficile infection all exhibit concurrent alterations in the composition of the gut microbiota and changes to host bile acid profiles. Similarly, extraintestinal diseases and syndromes such as asthma and obesity may be linked to aberrant bile acid profiles in the host. Here, we focus upon recent studies that highlight the links between alterations to gut microbial communities and altered bile acid profiles across a range of diseases from asthma to IBD.

scholarly journals Bile acid receptors FXR and TGR5 signaling in fatty liver diseases and therapy

2020 ◽  
Vol 318 (3) ◽  
pp. G554-G573 ◽  
Author(s):  
John Y. L. Chiang ◽  
Jessica M. Ferrell
Keyword(s):  
Bile Acid ◽  
Fatty Liver ◽  
Bile Acids ◽  
G Protein ◽  
Liver Diseases ◽  
Metabolic Diseases ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Bile Acid Receptors ◽  
G Protein Coupled

Bile acid synthesis is the most significant pathway for catabolism of cholesterol and for maintenance of whole body cholesterol homeostasis. Bile acids are physiological detergents that absorb, distribute, metabolize, and excrete nutrients, drugs, and xenobiotics. Bile acids also are signal molecules and metabolic integrators that activate nuclear farnesoid X receptor (FXR) and membrane Takeda G protein-coupled receptor 5 (TGR5; i.e., G protein-coupled bile acid receptor 1) to regulate glucose, lipid, and energy metabolism. The gut-to-liver axis plays a critical role in the transformation of primary bile acids to secondary bile acids, in the regulation of bile acid synthesis to maintain composition within the bile acid pool, and in the regulation of metabolic homeostasis to prevent hyperglycemia, dyslipidemia, obesity, and diabetes. High-fat and high-calorie diets, dysbiosis, alcohol, drugs, and disruption of sleep and circadian rhythms cause metabolic diseases, including alcoholic and nonalcoholic fatty liver diseases, obesity, diabetes, and cardiovascular disease. Bile acid-based drugs that target bile acid receptors are being developed for the treatment of metabolic diseases of the liver.

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

scholarly journals Tu1262 Obeticholic Acid, a Farnesoid X Receptor Agonist, Reduces Bile Acid Synthesis in Patients With Primary Bile Acid Diarrhea

2014 ◽  
Vol 146 (5) ◽  
pp. S-797 ◽  
Author(s):  
Claire Vassie ◽  
Jonathan D. Nolan ◽  
Ian M. Johnston ◽  
David Shapiro ◽  
Julian R. Walters
Keyword(s):  
Bile Acid ◽  
Receptor Agonist ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Farnesoid X Receptor ◽  
Obeticholic Acid ◽  
Primary Bile Acid

Identification of potential dual agonists of FXR and TGR5 using e-pharmacophore based virtual screening

2015 ◽  
Vol 11 (5) ◽  
pp. 1305-1318 ◽  
Author(s):  
Thangaraj Sindhu ◽  
Pappu Srinivasan
Keyword(s):  
Bile Acid ◽  
Virtual Screening ◽  
Drug Development ◽  
G Protein ◽  
Farnesoid X Receptor ◽  
G Protein Coupled Receptor ◽  
Treatment Of Diabetes ◽  
Bile Acid Receptors ◽  
G Protein Coupled

Farnesoid X receptor and Takeda G-protein-coupled receptor-5 are well known bile acid receptors and act as promising targets for the drug development and treatment of diabetes.

scholarly journals Role of bile acids in inflammatory liver diseases

2021 ◽  
Author(s):  
Ioannis Evangelakos ◽  
Joerg Heeren ◽  
Esther Verkade ◽  
Folkert Kuipers
Keyword(s):  
Bile Acid ◽  
Signaling Pathways ◽  
Bile Acids ◽  
Liver Diseases ◽  
Human Liver ◽  
Microbiome Composition ◽  
Acid Metabolites ◽  
Host Identification ◽  
Bile Acid Receptors ◽  
Metabolic Liver Diseases

AbstractBile acids and their signaling pathways are increasingly recognized as potential therapeutic targets for cholestatic and metabolic liver diseases. This review summarizes new insights in bile acid physiology, focusing on regulatory roles of bile acids in the control of immune regulation and on effects of pharmacological modulators of bile acid signaling pathways in human liver disease. Recent mouse studies have highlighted the importance of the interactions between bile acids and gut microbiome. Interfering with microbiome composition may be beneficial for cholestatic and metabolic liver diseases by modulating formation of secondary bile acids, as different bile acid species have different signaling functions. Bile acid receptors such as FXR, VDR, and TGR5 are expressed in a variety of cells involved in innate as well as adaptive immunity, and specific microbial bile acid metabolites positively modulate immune responses of the host. Identification of Cyp2c70 as the enzyme responsible for the generation of hydrophilic mouse/rat-specific muricholic acids has allowed the generation of murine models with a human-like bile acid composition. These novel mouse models will aid to accelerate translational research on the (patho)physiological roles of bile acids in human liver diseases .

scholarly journals Gut Dysbiosis and Abnormal Bile Acid Metabolism in Colitis-Associated Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Li Liu ◽  
Min Yang ◽  
Wenxiao Dong ◽  
Tianyu Liu ◽  
Xueli Song ◽  
...  
Keyword(s):  
Bile Acid ◽  
Gut Microbiota ◽  
Bile Acids ◽  
Acid Metabolism ◽  
Farnesoid X Receptor ◽  
Mucosal Barrier ◽  
Bile Acid Metabolism ◽  
Preventive Strategy ◽  
Gut Dysbiosis ◽  
Bile Acid Receptors

Background. Patients with prolonged inflammatory bowel disease (IBD) can develop into colorectal cancer (CRC), also called colitis-associated cancer (CAC). Studies have shown the association between gut dysbiosis, abnormal bile acid metabolism, and inflammation process. Here, we aimed to investigate these two factors in the CAC model. Methods. C57BL/6 mice were randomly allocated to two groups: azoxymethane/dextran sodium sulfate (AOM/DSS) and control. The AOM/DSS group received AOM injection followed by DSS drinking water. Intestinal inflammation, mucosal barrier, and bile acid receptors were determined by real-time PCR and immunohistochemistry. Fecal microbiome and bile acids were detected via 16S rRNA sequencing and liquid chromatography-mass spectrometry. Results. The AOM/DSS group exhibited severe mucosal barrier impairment, inflammatory response, and tumor formation. In the CAC model, the richness and biodiversity of gut microbiota were decreased, along with significant alteration of composition. The abundance of pathogens was increased, while the short-chain fatty acids producing bacteria were reduced. Interestingly, Clostridium XlV and Lactobacillus, which might be involved in the bile acid deconjugation, transformation, and desulfation, were significantly decreased. Accordingly, fecal bile acids were decreased, accompanied by reduced transformation of primary to secondary bile acids. Given bile acid receptors, the ileum farnesoid X receptor-fibroblast growth factor 15 (FXR-FGF15) axis was downregulated, while Takeda G-protein receptor 5 (TGR5) was overexpressed in colonic tumor tissues. Conclusion. Gut dysbiosis might alter the metabolism of bile acids and promote CAC, which would provide a potential preventive strategy of CAC by regulating gut microbiota and bile acid metabolism.

scholarly journals Intestinal bile acid receptors are key regulators of glucose homeostasis

2017 ◽  
Vol 76 (3) ◽  
pp. 192-202 ◽  
Author(s):  
Mohamed-Sami Trabelsi ◽  
Sophie Lestavel ◽  
Bart Staels ◽  
Xavier Collet
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Glucose Homeostasis ◽  
Energy Homeostasis ◽  
Acid Metabolism ◽  
Dietary Lipid ◽  
Farnesoid X Receptor ◽  
Bile Acid Metabolism ◽  
Metabolism Regulation ◽  
Bile Acid Receptors

In addition to their well-known function as dietary lipid detergents, bile acids have emerged as important signalling molecules that regulate energy homeostasis. Recent studies have highlighted that disrupted bile acid metabolism is associated with metabolism disorders such as dyslipidaemia, intestinal chronic inflammatory diseases and obesity. In particular, type 2 diabetes (T2D) is associated with quantitative and qualitative modifications in bile acid metabolism. Bile acids bind and modulate the activity of transmembrane and nuclear receptors (NR). Among these receptors, the G-protein-coupled bile acid receptor 1 (TGR5) and the NR farnesoid X receptor (FXR) are implicated in the regulation of bile acid, lipid, glucose and energy homeostasis. The role of these receptors in the intestine in energy metabolism regulation has been recently highlighted. More precisely, recent studies have shown that FXR is important for glucose homeostasis in particular in metabolic disorders such as T2D and obesity. This review highlights the growing importance of the bile acid receptors TGR5 and FXR in the intestine as key regulators of glucose metabolism and their potential as therapeutic targets.

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