title: Dual activation of the bile acid nuclear receptor FXR and G-protein-coupled receptor TGR5 protects mice against atherosclerosis.
abstract: Bile acid signaling is a critical regulator of glucose and energy metabolism, mainly through the nuclear receptor FXR and the G protein-coupled receptor TGR. The purpose of the present study was to investigate whether dual activation of FXR and TGR5 plays a significant role in the prevention of atherosclerosis progression. To evaluate the effects of bile acid signaling in atherogenesis, ApoE-/- mice and LDLR-/- mice were treated with an FXR/TGR5 dual agonist (INT-767). INT-767 treatment drastically reduced serum cholesterol levels. INT-767 treatment significantly reduced atherosclerotic plaque formation in both ApoE-/- and LDLR-/- mice. INT-767 decreased the expression of pro-inflammatory cytokines and chemokines in the aortas of ApoE-/- mice through the inactivation of NF-κB. In addition, J774 macrophages treated with INT-767 had significantly lower levels of active NF-κB, resulting in cytokine production in response to LPS through a PKA dependent mechanism. This study demonstrates that concurrent activation of FXR and TGR5 attenuates atherosclerosis by reducing both circulating lipids and inflammation.
authors.affiliation: Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, Colorado, United States of America.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Miyazaki-Anzai
authors.affiliation: Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, Colorado, United States of America.
authors.forename: Masashi
authors.initials: M
authors.lastname: Masuda
authors.affiliation: Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, Colorado, United States of America.
authors.forename: Moshe
authors.initials: M
authors.lastname: Levi
authors.affiliation: Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, Colorado, United States of America.
authors.forename: Audrey L
authors.initials: AL
authors.lastname: Keenan
authors.affiliation: Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, Colorado, United States of America.
authors.forename: Makoto
authors.initials: M
authors.lastname: Miyazaki
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism* / Q000494:pharmacology / Q000502:physiology; D002460:Cell Line; D002784:Cholesterol / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D014280:Triglycerides / Q000097:blood; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D002784:Cholesterol; D018160:Receptors, Cytoplasmic and Nuclear; D043562:Receptors, G-Protein-Coupled; D014280:Triglycerides; D000099150:Receptor, Farnesoid X-Activated; C000602622:6-ethyl-24-norcholane-3,7,23-triol-23 sulfate; C513561:Gpbar1 protein, mouse