Toll-like Receptor (TLR) Signaling Interacts with CREBH to Modulate High-density Lipoprotein (HDL) in Response to Bacterial Endotoxin
Toll-like Receptor (TLR) Signaling Interacts with CREBH to Modulate High-density Lipoprotein (HDL) in Response to Bacterial Endotoxin
复制标题
Toll样受体(TLR)信号与CREBH相互作用调节高密度脂蛋白(HDL)对细菌内毒素的反应
DOI：
10.1074/jbc.m116.755728
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发表时间：
2016-10-28
影响因子：
4.8
通讯作者：
Zhang, Kezhong
中科院分区：
文献类型：
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作者：
Dandekar, Aditya;Qiu, Yining;Zhang, Kezhong
细菌内毒素可引起宿主的炎症和代谢变化。在这项研究中，我们揭示了一种分子机制，通过这种机制，应激诱导的肝脏富集转录因子，camp响应元件结合蛋白肝特异性（CREBH），调节脂质谱，保护肝脏免受细菌内毒素脂多糖（LPS）的损伤。LPS刺激可以通过toll样受体(TLR)/ myd88依赖的方式激活小鼠肝组织中的CREBH。在LPS挑战下，CREBH与TNF受体相关因子6 （TRAF6）相互作用，TRAF6是一种E3泛素连接酶，作为TLR信号的关键介质，这种相互作用依赖于MyD88。进一步分析表明，TRAF6介导k63连接的CREBH泛素化，促进CREBH的裂解和激活。CREBH在LPS刺激下直接激活载脂蛋白A4 （ApoA4）基因的表达，导致动物体内高密度脂蛋白（HDL）的调节。CREBH缺乏导致循环HDL生成减少，并在高剂量LPS刺激下增加肝损伤。因此，TLR/ myd88依赖性、traf6促进的CREBH激活代表了哺乳动物通过调节HDL对细菌内毒素的肝脏防御反应。
Bacterial endotoxin can induce inflammatory and metabolic changes in the host. In this study, we revealed a molecular mechanism by which a stress-inducible, liver-enriched transcription factor, cAMP-responsive element-binding protein hepatic-specific (CREBH), modulates lipid profiles to protect the liver from injuries upon the bacterial endotoxin lipopolysaccharide (LPS). LPS challenge can activate CREBH in mouse liver tissues in a toll-like receptor (TLR)/MyD88-dependent manner. Upon LPS challenge, CREBH interacts with TNF receptor-associated factor 6 (TRAF6), an E3 ubiquitin ligase that functions as a key mediator of TLR signaling, and this interaction relies on MyD88. Further analysis demonstrated that TRAF6 mediates K63-linked ubiquitination of CREBH to facilitate CREBH cleavage and activation. CREBH directly activates expression of the gene encoding Apolipoprotein A4 (ApoA4) under LPS challenge, leading to modulation of high-density lipoprotein (HDL) in animals. CREBH deficiency led to reduced production of circulating HDL and increased liver damage upon high-dose LPS challenge. Therefore, TLR/MyD88-dependent, TRAF6-facilitated CREBH activation represents a mammalian hepatic defense response to bacterial endotoxin by modulating HDL.