Open AccessDual Activation of the Bile Acid Nuclear Receptor FXR and G-Protein-Coupled Receptor TGR5 Protects Mice against Atherosclerosis
Author(s) -
Shinobu Miyazaki–Anzai,
Masashi Masuda,
Moshe Levi,
Audrey L. Keenan,
Masaru Miyazaki
Publication year - 2014
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0108270
Subject(s) - g protein coupled bile acid receptor , medicine , endocrinology , agonist , nuclear receptor , receptor , bile acid , inflammation , liver x receptor , farnesoid x receptor , chemistry , chemokine , signal transduction , biology , biochemistry , transcription factor , gene
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.