Inhibition of NLRP3 inflammasome by thioredoxin-interacting protein in mouse Kupffer cells as a regulatory mechanism for non-alcoholic fatty liver disease development.
Inhibition of NLRP3 inflammasome by thioredoxin-interacting protein in mouse Kupffer cells as a regulatory mechanism for non-alcoholic fatty liver disease development.
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小鼠 Kupffer 细胞中硫氧还蛋白相互作用蛋白抑制 NLRP3 炎症小体作为非酒精性脂肪肝疾病发展的调节机制
DOI：
10.18632/oncotarget.17489
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发表时间：
2017-06-06
期刊：
影响因子：
--
通讯作者：
Gong J
中科院分区：
文献类型：
--
作者：
He K;Zhu X;Liu Y;Miao C;Wang T;Li P;Zhao L;Chen Y;Gong J;Cai C;Li J;Li S;Ruan XZ;Gong J
NOD样受体（NLR）NLRP 3炎性小体激活与非酒精性脂肪性肝病（NAFLD）从非酒精性脂肪肝（NAFL）到非酒精性脂肪性肝炎（NASH）的进展有关。研究还表明，棕榈酸（PA）激活Kupffer细胞（KCs）中的NLRP 3炎性体并促进白细胞介素-1 β（IL-1β）分泌。然而，NLRP 3炎性小体激活的具体机制尚不清楚。我们通过研究硫氧还蛋白相互作用蛋白（TXNIP）和NLRP 3在患者NAFLD发展中的作用，高脂饮食（HFD）诱导的NAFL和蛋氨酸胆碱缺乏（MCD）饮食诱导的NASH在野生型（WT），TXNIP−/−（硫氧还蛋白相互作用蛋白）和NLRP 3 −/−小鼠以及分离的KC中的作用来研究分子机制。结果发现NASH组肝组织NLRP 3和TXNIP的表达均高于NAFL组。此外，免疫共沉淀分析显示，TXNIP-NLRP 3炎性体蛋白复合物的活化发生在NASH WT小鼠而不是NAFL WT小鼠的KC中，因此表明该蛋白复合物的形成和活化主要参与NASH的发展。在MCD饮食模型中，NLRP 3 −/−小鼠表现出比WT小鼠更轻的NASH，而TXNIP缺乏增强了NLRP 3炎性小体激活并加重了肝损伤。PA触发了从WT和TXNIP−/−小鼠分离的KC中NLRP 3炎性体蛋白复合物的激活和共定位，但没有NLRP 3 −/−小鼠，并且PA刺激后大部分复合物与KC的线粒体共定位。总之，我们的新发现表明，TXNIP通过结合和抑制NLRP 3在NAFLD的发展中发挥保护和抗炎作用。
NOD-like receptor (NLR) NLRP3 inflammasome activation has been implicated in the progression of non-alcoholic fatty liver disease (NAFLD) from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH). It has been also shown that palmitic acid (PA) activates NLRP3 inflammasome and promotes interleukin-1β (IL-1β) secretion in Kupffer cells (KCs). However, the specific mechanism of the NLRP3 inflammasome activation is unclear. We studies the molecular mechanisms by investigating the roles of Thioredoxin-interacting protein (TXNIP) and NLRP3 on NAFLD development in patients, high-fat diet (HFD)-induced NAFL and methionine choline deficient (MCD) diet-induced NASH in wild type (WT), TXNIP−/−(thioredoxin-interacting protein) and NLRP3−/− mice, and isolated KCs. We found that the expressions of NLRP3 and TXNIP in human liver tissues were higher in NASH group than in NAFL group. Furthermore, co-immunoprecipitation analyses show that activation of the TXNIP-NLRP3 inflammasome protein complex occurred in KCs of NASH WT mice rather than NAFL WT mice, thus suggesting that the formation and activation of this protein complex is mainly involved in the development of NASH. NLRP3−/− mice exhibited less severe NASH than WT mice in MCD diet model, whereas TXNIP deficiency enhanced NLRP3 inflammasome activation and exacerbated liver injury. PA triggered the activation and co-localization of the NLRP3 inflammasome protein complex in KCs isolated from WT and TXNIP−/− but not NLRP3−/− mice, and most of the complex co-localized with mitochondria of KCs following PA stimulation. Taken together, our novel findings indicate that TXNIP plays a protective and anti-inflammatory role in the development of NAFLD through binding and suppressing NLRP3.
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影响因子：
32.4
作者：
Iyer SS;He Q;Janczy JR;Elliott EI;Zhong Z;Olivier AK;Sadler JJ;Knepper-Adrian V;Han R;Qiao L;Eisenbarth SC;Nauseef WM;Cassel SL;Sutterwala FS
通讯作者：
Sutterwala FS
影响因子：
25.7
作者：
Hoque, Rafaz;Vodovotz, Yoram;Mehal, Wajahat
通讯作者：
Mehal, Wajahat
影响因子：
13.5
作者：
Csak, Timea;Ganz, Michal;Pespisa, Justin;Kodys, Karen;Dolganiuc, Angela;Szabo, Gyongyi
通讯作者：
Szabo, Gyongyi
影响因子：
4.4
作者：
Li, Pei-zhi;Li, Jin-zheng;He, Kun
通讯作者：
He, Kun
活性氧诱导的 TXNIP 通过 NLRP3 炎症小体激活驱动果糖介导的肝脏炎症和脂质积累。
影响因子：
6.6
作者：
Zhang, Xian;Zhang, Jian-Hua;Kong, Ling-Dong
通讯作者：
Kong, Ling-Dong