TGR5 Activation Inhibits Atherosclerosis by Reducing Macrophage Inflammation and Lipid Loading

被引：528

作者：

Pols, Thijs W. H. ^{[1
]}

Nomura, Mitsunori ^{[1
]}

Harach, Taoufiq ^{[1
]}

Lo Sasso, Giuseppe ^{[1
]}

Oosterveer, Maaike H. ^{[1
]}

Thomas, Charles ^{[1
]}

Rizzo, Giovanni ^{[2
]}

Gioiello, Antimo ^{[3
]}

Adorini, Luciano ^{[2
]}

Pellicciari, Roberto ^{[3
]}

Auwerx, Johan ^{[1
]}

Schoonjans, Kristina ^{[1
]}

机构：

[1] Ecole Polytech Fed Lausanne, Lab Integrat & Syst Physiol, CH-1015 Lausanne, Switzerland

[2] Intercept Pharmaceut, New York, NY 10013 USA

[3] Univ Perugia, Dipartimento Chim & Tecnol Farmaco, I-06123 Perugia, Italy

来源：

CELL METABOLISM | 2011年 / 14卷 / 06期

基金：

瑞士国家科学基金会; 欧洲研究理事会;

关键词：

BILE-ACID RECEPTOR; NF-KAPPA-B; MICE; PROTEIN; GPBAR1; AGONIST; CELLS; DELETION; LESION;

D O I：

10.1016/j.cmet.2011.11.006

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 6 alpha-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-kappa B inhibition. TGR5 activation attenuated atherosclerosis in Ld/r(-/-)Tgr5(+/+) mice but not in Ld/r(-/-)Tgr5(-/-) double-knockout mice. The inhibition of lesion formation was associated with decreased intraplaque inflammation and less plaque macrophage content. Furthermore, Ld/r(-/-)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.

引用

页码：747 / 757

页数：11

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