TGR5 reduces macrophage migration through mTOR-induced C/EBPβ differential translation
TGR5 reduces macrophage migration through mTOR-induced C/EBPβ differential translation
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DOI：
10.1172/jci76289
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发表时间：
2014-12-01
影响因子：
15.9
通讯作者：
Schoonjans, Kristina
中科院分区：
文献类型：
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作者：
Perino, Alessia;Pols, Thijs Willem Hendrik;Schoonjans, Kristina
胆汁酸反应的G蛋白偶联受体TGR5参与了几个代谢过程，最近的研究表明，TGR5的激活可能促进了预防饮食诱导的糖尿病的途径。在这里，我们研究了巨噬细胞特异性TGR5信号在保护脂肪组织免受炎症和相关的胰岛素抵抗中的作用。对缺乏巨噬细胞TGR5的肥胖小鼠的脂肪组织的检查显示，与对照肥胖动物相比，炎症增强，趋化因子表达增加，巨噬细胞数量增加。此外，巨噬细胞特异性的TGR5缺失加剧了肥胖动物的胰岛素抵抗。相反，TGR5的药理激活可显著降低脂多糖诱导的巨噬细胞趋化因子的表达。这种降低是通过依赖于AKT的mTOR复合体1的激活来介导的，mTOR复合体1反过来又诱导了显性-阴性C/EBPβ亚型-肝脏抑制蛋白(LIP)的差异翻译。总体而言，这些研究揭示了TGR5下游的一条信号通路，该通路调节趋化因子的表达以响应高脂肪饮食，并表明靶向这一通路有可能被用于预防慢性炎症性疾病和2型糖尿病的治疗。
The bile acid-responsive G protein-coupled receptor TGR5 is involved in several metabolic processes, and recent studies suggest that TGR5 activation may promote pathways that are protective against diet-induced diabetes. Here, we investigated the role of macrophage-specific TGR5 signaling in protecting adipose tissue from inflammation and associated insulin resistance. Examination of adipose tissue from obese mice lacking macrophage Tgr5 revealed enhanced inflammation, increased chemokine expression, and higher macrophage numbers compared with control obese animals. Moreover, macrophage-specific deletion of Tgr5 exacerbated insulin resistance in obese animals. Conversely, pharmacological activation of TGR5 markedly decreased LPS-induced chemokine expression in primary macrophages. This reduction was mediated by AKT-dependent activation of mTOR complex 1, which in turn induced the differential translation of the dominant-negative C/EBP beta isoform, liver inhibitory protein (LIP). Overall, these studies reveal a signaling pathway downstream of TGR5 that modulates chemokine expression in response to high-fat diet and suggest that targeting this pathway has the potential to be therapeutically exploited for prevention of chronic inflammatory diseases and type 2 diabetes mellitus.