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Updated: Jul 10, 2025
Optimized Analysis of In Vivo and In Vitro Hepatic Steatosis
Published on: March 11, 2017
Defective Bile Acid Signaling Promotes Vascular Dysfunction, Supporting a Role for G-Protein Bile Acid Receptor
Silvia Marchianò1, Michele Biagioli1, Martina Bordoni1
1Department of Medicine and Surgery University of Perugia Perugia Italy.
Background:
Patients with nonalcoholic fatty liver disease are at increased risk to develop atherosclerotic cardiovascular diseases. FXR and GPBAR1 are 2 bile acid-activated receptors exploited in the treatment of nonalcoholic fatty liver disease: whether dual GPBAR1/FXR agonists synergize with statins in the treatment of the liver and cardiovascular components of nonalcoholic fatty liver disease is unknown.
Methods And Results:
Investigations of human aortic samples obtained from patients who underwent surgery for aortic aneurysms and Gpbar1-/-, Fxr-/-, and dual Gpbar1-/-Fxr-/- mice demonstrated that GPBAR1 and FXR are expressed in the aortic wall and regulate endothelial cell/macrophage interactions. The expression of GPBAR1 in the human endothelium correlated with the expression of inflammatory biomarkers. Mice lacking Fxr and Gpbar1-/-/Fxr-/- display hypotension and aortic inflammation, along with altered intestinal permeability that deteriorates with age, and severe dysbiosis, along with dysregulated bile acid synthesis. Vasomotor activities of aortic rings were altered by Gpbar1 and Fxr gene ablation. In apolipoprotein E-/- and wild-type mice, BAR502, a dual GPBAR1/FXR agonist, alone or in combination with atorvastatin, reduced cholesterol and low-density lipoprotein plasma levels, mitigated the development of liver steatosis and aortic plaque formation, and shifted the polarization of circulating leukocytes toward an anti-inflammatory phenotype. BAR502/atorvastatin reversed intestinal dysbiosis and dysregulated bile acid synthesis, promoting a shift of bile acid pool composition toward FXR antagonists and GPBAR1 agonists.
Conclusions:
FXR and GPBAR1 maintain intestinal, liver, and cardiovascular homeostasis, and their therapeutic targeting with a dual GPBAR1/FXR ligand and atorvastatin holds potential in the treatment of liver and cardiovascular components of nonalcoholic fatty liver disease.
Insights
Dual GPBAR1/FXR agonists combined with statins show promise for treating nonalcoholic fatty liver disease and related cardiovascular issues by improving liver health and reducing inflammation.
Area of Science:
- Cardiovascular Medicine
- Hepatology
- Pharmacology
Background:
- Nonalcoholic fatty liver disease (NAFLD) patients face heightened risks of atherosclerotic cardiovascular diseases.
- Bile acid-activated receptors, FXR and GPBAR1, are therapeutic targets for NAFLD.
- The synergistic effects of dual GPBAR1/FXR agonists with statins on NAFLD's liver and cardiovascular aspects remain unexplored.
Purpose of the Study:
- To investigate the potential synergistic effects of dual GPBAR1/FXR agonists and statins in managing NAFLD.
- To evaluate the impact of targeting GPBAR1 and FXR on cardiovascular health in the context of NAFLD.
Main Methods:
- Human aortic samples and genetically modified mice (Gpbar1-/-, Fxr-/-, Gpbar1-/-Fxr-/-) were used to study GPBAR1 and FXR expression and function in the aortic wall.
- BAR502, a dual GPBAR1/FXR agonist, was tested alone and with atorvastatin in apolipoprotein E-/- mice to assess its effects on lipid levels, liver steatosis, and aortic plaque formation.
- Analyses included plasma lipid profiles, leukocyte polarization, intestinal permeability, gut microbiota composition, bile acid synthesis, and aortic vasomotor activity.
Main Results:
- GPBAR1 and FXR are expressed in the aortic wall, influencing endothelial cell-macrophage interactions and correlating with inflammatory biomarkers.
- Mice lacking Fxr or both Gpbar1 and Fxr exhibited hypotension, aortic inflammation, increased intestinal permeability, dysbiosis, and altered bile acid metabolism.
- BAR502, with or without atorvastatin, reduced plasma cholesterol and LDL, mitigated liver steatosis and aortic plaque, promoted anti-inflammatory leukocyte polarization, and corrected gut dysbiosis and bile acid dysregulation.
Conclusions:
- FXR and GPBAR1 play crucial roles in maintaining intestinal, liver, and cardiovascular homeostasis.
- Therapeutic strategies involving dual GPBAR1/FXR ligands in combination with statins present a promising approach for treating both the hepatic and cardiovascular complications associated with NAFLD.
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