Related Experiment Videos

Benefit of farnesoid X receptor inhibition in obstructive cholestasis

Catherine Stedman1, Christopher Liddle, Sally Coulter

  • 1Department of Clinical Pharmacology, Molecular Pharmacology Laboratory, Westmead Millennium Institute, Westmead Hospital, University of Sydney, Sydney NSW 2145, Australia.

Proceedings of the National Academy of Sciences of the United States of America
|July 18, 2006
PubMed

Insights

Farnesoid X receptor (FXR) protects against cholestatic liver injury by regulating bile acids and hepatic transporters. FXR antagonists may treat obstructive cholestatic liver disorders.

Area of Science:

  • Hepatology and Molecular Endocrinology
  • Nuclear Receptor Signaling

Background:

  • Nuclear hormone receptors, including farnesoid X receptor (FXR) and pregnane X receptor, regulate key metabolic pathways.
  • Bile acid metabolism and cholestatic liver injury are complex processes influenced by these receptors.

Purpose of the Study:

  • To investigate the role of FXR in modulating cholestatic liver injury.
  • To evaluate the therapeutic potential of targeting FXR in liver disorders.

Main Methods:

  • Utilized bile duct ligation in mice to induce cholestasis and increase endogenous bile acids.
  • Employed FXR knockout (KO) mouse models to assess the receptor's protective or detrimental effects.
  • Analyzed alterations in hepatic transporters (Mdr1, Mdr2, BSEP, Mrp4) and lipid profiles.

Main Results:

  • FXR knockout mice demonstrated protection against obstructive cholestasis and associated liver injury.
  • Deletion of FXR ameliorated liver injury in pregnane X receptor knockout mice during cholestasis.
  • FXR modulation was linked to reduced bile acid concentrations, altered transporter expression, and biphasic lipid profiles, including triglyceride regulation.

Conclusions:

  • FXR plays a critical role in managing bile acid homeostasis within hepatocytes.
  • FXR influences bile acid synthesis, excretion via BSEP, and serum export via Mrp4.
  • FXR antagonists represent a promising therapeutic strategy for obstructive cholestatic liver diseases.

Related Concept Videos

Indirect-Acting Cholinergic Agonists: Pharmacological Actions01:30

Indirect-Acting Cholinergic Agonists: Pharmacological Actions

Indirect-acting cholinergic agonists, also known as anticholinesterases, exert their pharmacological effects by enhancing cholinergic transmission in various body parts, including the neuromuscular junction, autonomic cholinergic synapses, and the brain.
At the neuromuscular junction, these agents work by inhibiting the breakdown of acetylcholine, allowing it to remain bound to the receptor and bind to nearby receptors. This process leads to repetitive firing of the endplate, causing muscle...
Indirect-Acting Cholinergic Agonists: Mechanism of Action01:18

Indirect-Acting Cholinergic Agonists: Mechanism of Action

Indirect-acting cholinergic agonists work by interacting with an enzyme called acetylcholinesterase (AChE) in the synaptic cleft. They can be reversible or irreversible inhibitors and have different effects on the enzyme.
Reversible inhibitors like edrophonium bind to a specific part of the enzyme called the anionic catalytic site. They form noncovalent bonds, which means they are not strongly attached to the enzyme. This creates a temporary and less stable enzyme–inhibitor complex, leading to...
Direct-Acting Cholinergic Agonists: Therapeutic Uses01:11

Direct-Acting Cholinergic Agonists: Therapeutic Uses

Direct-acting cholinergic agonists have many therapeutic uses in various medical fields. Choline esters, including acetylcholine, have limited clinical utility due to their non-selectivity and short duration of action. Still, acetylcholine and carbachol are applied topically during ophthalmologic surgery to induce miosis. Pilocarpine, a muscarinic and ganglionic stimulator, effectively treats open-angle glaucoma and alleviates xerostomia and dry mouth caused by radiotherapy or Sjögren syndrome.
Hepatic Drug Excretion: Enterohepatic Cycling01:17

Hepatic Drug Excretion: Enterohepatic Cycling

Enterohepatic cycling involves the active secretion of drugs and their metabolites into the bile via transporters in the canalicular membrane of hepatocytes. This secretion is an integral part of the digestive process, releasing these substances into the gastrointestinal (GI) tract.
Post-release drugs and metabolites can be reabsorbed into the body from the intestine. For conjugated metabolites like glucuronides, reabsorption requires enzymatic hydrolysis by intestinal microflora. This...
Chemotherapy-Induced Nausea and Vomiting: 5-HT3 Receptor Antagonists01:27

Chemotherapy-Induced Nausea and Vomiting: 5-HT3 Receptor Antagonists

5-HT3 receptor antagonists, such as dolasetron, granisetron (Kytril), ondansetron (Zofran), and palonosetron (Axoli), are crucial in managing chemotherapy-induced nausea and vomiting (CINV) and postoperative nausea. These drugs selectively block 5-HT3 receptors in the visceral vagal and spinal afferent nerves, chemoreceptor trigger zone, and the vomiting center. They have a rapid onset of action and can be given as a single dose before chemotherapy. Ondansetron and granisetron, in particular,...