Related Experiment Video
Updated: Sep 11, 2025
09:21
Real Time Monitoring of Intracellular Bile Acid Dynamics Using a Genetically Encoded FRET-based Bile Acid Sensor
Published on: January 4, 2016
10.0K
Structural Basis of Novel Bile Acid-Based Modulators of FXR
D Kydd-Sinclair1, G L Packer2, A C Weymouth-Wilson3
1School of Biological Sciences, Health and Life Sciences Building, Whiteknights Campus, University of Reading, Reading, Berkshire RG6 6EX, UK.
Journal of Molecular Biology
|August 13, 2025
Summary
Two novel bile acid derivatives show potent and selective farnesoid X receptor (FXR) activation, offering potential for gene-specific regulation in liver diseases and overcoming limitations of current drugs.
Area of Science:
- Hepatology and Pharmacology
- Molecular Biology and Biochemistry
- Drug Discovery and Development
Background:
- Farnesoid X receptor (FXR) regulates key metabolic and inflammatory pathways implicated in liver diseases.
- Current FXR agonists like obeticholic acid face challenges due to systemic activation and adverse effects.
- Selective modulation of FXR signaling is crucial for developing safer and more effective therapeutics.
Purpose of the Study:
- To validate and characterize two novel bile acid derivatives as selective FXR agonists.
- To investigate their binding modes, coactivator recruitment, and downstream signaling effects in vitro and in vivo.
- To assess their potential to overcome the limitations of existing FXR-targeting drugs.
Main Methods:
- X-ray crystallography to determine co-crystal structures of FXR ligand-binding domain (LBD) with novel compounds.
- LanthaScreen coactivator recruitment assays to assess ligand-dependent activation.
- In vitro studies using hepatocellular carcinoma cells to analyze gene expression changes (RNA sequencing, RT-qPCR).
- In vivo studies in C57BL/6 mice to evaluate compound effects on FXR signaling pathways.
Main Results:
- Novel compounds demonstrated potent and selective FXR agonist activity, exceeding obeticholic acid in potency.
- Distinct binding modes were observed, including allosteric activation via a receptor sub-pocket.
- Compounds induced greater FXR target gene expression changes at lower doses compared to obeticholic acid.
- Differential gene expression patterns were observed in vivo, suggesting compound-specific regulatory effects.
Conclusions:
- The novel bile acid derivatives exhibit unique binding and activation properties, enabling gene-specific FXR regulation.
- These compounds hold promise for developing improved therapeutics for liver diseases by overcoming the adverse effects of systemic FXR activation.
- Further research is warranted to explore their full therapeutic potential.
Related Concept Videos
01:31Transducer Mechanism: Nuclear Receptors
1.6K
Nuclear receptors, or NRs, are unique transcription factors that regulate gene transcription and affect the cellular pathways involved in reproduction, development, or metabolism. Their ability to be stimulated by small lipophilic ligands and control vital cellular processes makes them ideal drug targets. Nearly 10-15% of currently prescribed drugs target these receptors.
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:
1.6K
01:16Hepatic Drug Excretion: Influencing Factors
218
The biliary system of the liver, crucial for bile secretion and drug excretion, comprises intrahepatic bile ducts that merge to form the common hepatic duct. This duct, carrying hepatic bile, combines with the cystic duct, draining the gallbladder and forming the common bile duct, which empties into the duodenum. Bile, produced by hepatic cells lining the bile canaliculi, is composed primarily of water, bile salts, pigments, electrolytes, and lesser amounts of cholesterol and fatty acids. Bile...
218
01:20Lipid-Lowering Drugs: Statins and Miscellaneous Agents
871
Hyperlipidemia, a medical condition often referred to as high cholesterol, is characterized by abnormally elevated levels of lipids in the bloodstream. When present in excess, these lipids, specifically cholesterol and triglycerides, can lead to serious health complications, often involving cardiovascular diseases. Illnesses like atherosclerosis, heart attacks, and pancreatitis have all been linked to untreated hyperlipidemia. This means controlling and regulating cholesterol and triglyceride...
871
01:28Overview of Fatty Acid Metabolism
31.7K
Lipids also are sources of energy that power cellular processes. Like carbohydrates, lipids are composed of carbon, hydrogen, and oxygen, but these atoms are arranged differently. Most lipids are nonpolar and hydrophobic. Major types include fats and oils, waxes, phospholipids, and steroids.
Fatty acids are catabolized in a process called beta-oxidation, which takes place in the matrix of the mitochondria and converts their fatty acid chains into two-carbon units of acetyl groups. The acetyl...
Fatty acids are catabolized in a process called beta-oxidation, which takes place in the matrix of the mitochondria and converts their fatty acid chains into two-carbon units of acetyl groups. The acetyl...
31.7K
01:24Principles of Drug Action
6.6K
Drugs are chemical substances that modify biological responses by interacting with macromolecular targets such as receptors, ion channels, transporters, and enzymes. Pharmacodynamics describes the course of action of drugs leading to the physiological effect at a specific site in the body.
Drugs can be agonists or antagonists. Like the endogenous ligands, agonists always bind and activate the target to produce a cellular response. Agonist binding induces a conformational change which in turn...
Drugs can be agonists or antagonists. Like the endogenous ligands, agonists always bind and activate the target to produce a cellular response. Agonist binding induces a conformational change which in turn...
6.6K
01:07Physiological Pharmacokinetic Models: Incorporating Hepatic Transporter-Mediated Clearance
80
Drug transporters are critical in drug absorption, distribution, and excretion processes. They should be included in physiological-based pharmacokinetic (PBPK) models, which help predict human drug disposition. However, predicting this is challenging during drug development, especially when liver transport is involved. However, with a realistic representation of body transport processes, an accurate model may be possible.
A recent model describes pravastatin's hepatobiliary excretion,...
A recent model describes pravastatin's hepatobiliary excretion,...
80