A role of the bile salt receptor FXR in atherosclerosis.
This study reviews current insights into the role of bile salts and bile salt receptors on the progression and regression of atherosclerosis. Bile salts have emerged as important modifiers of lipid and energy metabolism. At the molecular level, bile salts regulate lipid and energy homeostasis mainly via the bile salt receptors FXR and TGR5. Activation of FXR has been shown to improve plasma lipid profiles, whereas Fxr(-/-) mice have increased plasma triglyceride and very-low-density lipoprotein levels. Nevertheless, high-density lipoprotein cholesterol levels are increased in these mice, suggesting that FXR has both anti- and proatherosclerotic properties. Interestingly, there is increasing evidence for a role of FXR in "nonclassical" bile salt target tissues, eg, vasculature and macrophages. In these tissues, FXR has been shown to influence vascular tension and regulate the unloading of cholesterol from foam cells, respectively. Recent publications have provided insight into the antiinflammatory properties of FXR in atherosclerosis. Bile salt signaling via TGR5 might regulate energy homeostasis, which could serve as an attractive target to increase energy expenditure and weight loss. Interventions aiming to increase cholesterol turnover (eg, by bile salt sequestration) significantly improve plasma lipid profiles and diminish atherosclerosis in animal models. Bile salt metabolism and bile salt signaling pathways represent attractive therapeutic targets for the treatment of atherosclerosis.
Hageman
Jurre
J
Laboratory of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University Medical Center Groningen, Hanzeplein 1, 9713 EZ Groningen, The Netherlands. j.hageman@med.umcg.nl
Herrema
Hilde
H
Groen
Albert K
AK
Kuipers
Folkert
F
D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D001647:Bile Acids and Salts / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D004734:Energy Metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008264:Macrophages / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D009765:Obesity / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction; D000099150:Receptor, Farnesoid X-Activated
D001647:Bile Acids and Salts; D018836:Inflammation Mediators; D008055:Lipids; D018160:Receptors, Cytoplasmic and Nuclear; D043562:Receptors, G-Protein-Coupled; D000099150:Receptor, Farnesoid X-Activated; C473772:GPBAR1 protein, human