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A Familial Hypercholesterolemia Human Liver Chimeric Mouse Model Using Induced Pluripotent Stem Cell-derived Hepatocytes
Published on: September 15, 2018
Prevention of cholesterol gallstone disease by FXR agonists in a mouse model
Antonio Moschetta1, Angie L Bookout, David J Mangelsdorf
1Howard Hughes Medical Institute and Department of Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9050, USA.
Abstract:
Cholesterol gallstone disease is characterized by several events, including cholesterol precipitation in bile, increased bile salt hydrophobicity and gallbladder inflammation. Here, we describe the same phenotype in mice lacking the bile acid receptor, FXR. Furthermore, in susceptible wild-type mice that recapitulate human cholesterol gallstone disease, treatment with a synthetic FXR agonist prevented sequelae of the disease. These effects were mediated by FXR-dependent increases in biliary bile salt and phospholipid concentrations, which restored cholesterol solubility and thereby prevented gallstone formation. Taken together, these results indicate that FXR is a promising therapeutic target for treating or preventing cholesterol gallstone disease.
Insights
Cholesterol gallstone disease involves bile precipitation and inflammation. Targeting the bile acid receptor FXR in mice prevented gallstones by increasing cholesterol solubility, suggesting FXR as a therapeutic target.
Area of Science:
- Hepatology and Gastroenterology
- Molecular Biology
- Pharmacology
Background:
- Cholesterol gallstone disease is a common condition characterized by cholesterol precipitation, increased bile salt hydrophobicity, and gallbladder inflammation.
- The precise molecular mechanisms underlying gallstone formation are not fully understood.
Purpose of the Study:
- To investigate the role of the Farnesoid X Receptor (FXR) in cholesterol gallstone disease pathogenesis.
- To evaluate the therapeutic potential of FXR agonists in preventing gallstone formation.
Main Methods:
- Phenotypic analysis of mice lacking the bile acid receptor, FXR.
- Treatment of susceptible wild-type mice with a synthetic FXR agonist.
- Assessment of biliary cholesterol solubility and gallstone formation.
Main Results:
- Mice lacking FXR exhibited a phenotype mirroring cholesterol gallstone disease, including cholesterol precipitation and gallbladder inflammation.
- Treatment with a synthetic FXR agonist prevented gallstone formation in susceptible mice.
- FXR activation led to increased biliary bile salt and phospholipid concentrations, enhancing cholesterol solubility.
Conclusions:
- FXR plays a critical role in regulating cholesterol metabolism and solubility in bile.
- FXR agonists represent a promising therapeutic strategy for preventing and treating cholesterol gallstone disease.
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