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TGR5 activation inhibits atherosclerosis by reducing macrophage inflammation and lipid loading.

机译:TGR5激活通过减少巨噬细胞炎症和脂质负荷来抑制动脉粥样硬化。

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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 6alpha-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-kappaB 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.
机译:已将G蛋白偶联受体TGR5鉴定为胆汁酸信号网络的重要组成部分,其激活与提高能量消耗和改善血糖控制有关。在这里,我们证明了半合成BA6α-乙基-23(S)-甲基胆酸(6-EMCA,INT-777)对巨噬细胞中TGR5的激活抑制了促炎细胞因子的产生,这是由TGR5诱导的cAMP信号介导的以及随后的NF-κB抑制作用。 TGR5激活减弱了Ldlr(-/-)Tgr5(+ / +)小鼠的动脉粥样硬化,但不适用于Ldlr(-/-)Tgr5(-/-)双敲除小鼠。抑制病变形成与减少斑块内炎症和减少斑块巨噬细胞含量有关。此外,移植有Tgr5(-/-)骨髓的Ldlr(-/-)动物没有显示出INT-777对动脉粥样硬化的抑制作用,进一步确立了白细胞在INT-777介导的血管病变形成抑制中的重要作用。综上所述,在预防动脉粥样硬化(代谢综合征的重要方面)方面,这些数据将重要的免疫调节功能归因于TGR5激活。

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