title: TGR5 activation inhibits atherosclerosis by reducing macrophage inflammation and lipid loading.
abstract: The G protein-coupled receptor TGR5 has been identified as an important component of the bile acid signaling network, and its activation has been linked to enhanced energy expenditure and improved glycemic control. Here, we demonstrate that activation of TGR5 in macrophages by 6α-ethyl-23(S)-methylcholic acid (6-EMCA, INT-777), a semisynthetic BA, inhibits proinflammatory cytokine production, an effect mediated by TGR5-induced cAMP signaling and subsequent NF-κB inhibition. TGR5 activation attenuated atherosclerosis in Ldlr(-/-)Tgr5(+/+) mice but not in Ldlr(-/-)Tgr5(-/-) double-knockout mice. The inhibition of lesion formation was associated with decreased intraplaque inflammation and less plaque macrophage content. Furthermore, Ldlr(-/-) animals transplanted with Tgr5(-/-) bone marrow did not show an inhibition of atherosclerosis by INT-777, further establishing an important role of leukocytes in INT-777-mediated inhibition of vascular lesion formation. Taken together, these data attribute a significant immune modulating function to TGR5 activation in the prevention of atherosclerosis, an important facet of the metabolic syndrome.
authors.affiliation: Laboratory of Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Thijs W H
authors.initials: TW
authors.lastname: Pols
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Nomura
authors.forename: Taoufiq
authors.initials: T
authors.lastname: Harach
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lo Sasso
authors.forename: Maaike H
authors.initials: MH
authors.lastname: Oosterveer
authors.forename: Charles
authors.initials: C
authors.lastname: Thomas
authors.forename: Giovanni
authors.initials: G
authors.lastname: Rizzo
authors.forename: Antimo
authors.initials: A
authors.lastname: Gioiello
authors.forename: Luciano
authors.initials: L
authors.lastname: Adorini
authors.forename: Roberto
authors.initials: R
authors.lastname: Pellicciari
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
authors.forename: Kristina
authors.initials: K
authors.lastname: Schoonjans
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D050197:Atherosclerosis / Q000473:pathology / Q000517:prevention & control*; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D002793:Cholic Acids / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D016207:Cytokines / Q000037:antagonists & inhibitors*; D017931:DNA Primers / Q000235:genetics; D005434:Flow Cytometry; D007150:Immunohistochemistry; D061346:Laser Capture Microdissection; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D060888:Real-Time Polymerase Chain Reaction; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C545501:6alpha-ethyl-23(S)-methylcholic acid; D002793:Cholic Acids; D016207:Cytokines; D017931:DNA Primers; C513561:Gpbar1 protein, mouse; D016328:NF-kappa B; D043562:Receptors, G-Protein-Coupled; D000242:Cyclic AMP