炎症体
败血症
胆汁淤积
法尼甾体X受体
胆汁酸
G蛋白偶联胆汁酸受体
受体
下调和上调
医学
内科学
生物
生物化学
核受体
转录因子
基因
作者
Haiping Hao,Lijuan Cao,Changtao Jiang,Yuan Che,Song‐Yang Zhang,Shogo Takahashi,Guangji Wang,Frank J. Gonzalez
出处
期刊:Cell Metabolism
[Elsevier]
日期:2017-04-01
卷期号:25 (4): 856-867.e5
被引量:295
标识
DOI:10.1016/j.cmet.2017.03.007
摘要
Summary
Cholestasis is a common complication of sepsis, and the increased plasma levels of bile acids are predictive of sepsis-associated mortality. However, the exact mechanism by which cholestasis aggravates sepsis development remains elusive. Here, we show that bile acids are danger-associated molecular patterns (DAMPs) that can activate both signal 1 and 2 of the NLRP3 inflammasome in inflammatory macrophages. Mechanistically, bile acids induce a prolonged calcium influx and activate the NLRP3 inflammasome synergistically with ATP. Experimental cholestasis sensitizes, while cholestyramine, a bile acid sequestrant, protects mice from LPS-induced sepsis. FXR negatively regulates the NLRP3 inflammasome via physical interaction with NLRP3 and caspase 1. Fxr-null mice are more sensitive, while FXR-overexpressing mice are more resistant, to endoxemia shock. These findings suggest that bile acids and FXR play pivotal roles in sepsis via controlling the NLRP3 inflammasome, and that targeting FXR may represent a therapeutic strategy for cholestasis-associated sepsis.
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