He Kun, Zhu Xiwen, Liu Yan, Miao Chunmu, Wang Tao, Li Peizhi, Zhao Lei, Chen Yaxi, Gong Junhua, Cai Can, Li Jinzheng, Li Shengwei, Ruan Xiong Z, Gong Jianping
Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Oncotarget. 2017 Jun 6;8(23):37657-37672. doi: 10.18632/oncotarget.17489.
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.
核苷酸结合寡聚化结构域样受体（NLR）NLRP3炎性小体的激活与非酒精性脂肪性肝病（NAFLD）从非酒精性脂肪肝（NAFL）进展为非酒精性脂肪性肝炎（NASH）有关。研究还表明，棕榈酸（PA）可激活NLRP3炎性小体并促进库普弗细胞（KC）中白细胞介素-1β（IL-1β）的分泌。然而，NLRP3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NLRP3在野生型（WT）、TXNIP基因敲除（thioredoxin-interacting protein）和NLRP3基因敲除小鼠以及分离的KC中患者非酒精性脂肪性肝病发展、高脂饮食（HFD）诱导的NAFL和蛋氨酸胆碱缺乏（MCD）饮食诱导的NASH中的作用，来研究其分子机制。我们发现，NASH组人肝组织中NLRP3和TXNIP的表达高于NAFL组。此外，免疫共沉淀分析表明，TXNIP-NLRP3炎性小体蛋白复合物的激活发生在NASH WT小鼠的KC中，而非NAFL WT小鼠的KC中，因此表明该蛋白复合物的形成和激活主要参与NASH的发展。在MCD饮食模型中，NLRP3基因敲除小鼠的NASH严重程度低于WT小鼠，而TXNIP缺乏增强了NLRP3炎性小体的激活并加剧了肝损伤。PA触发了从WT和TXNIP基因敲除小鼠而非NLRP3基因敲除小鼠分离的KC中NLRP3炎性小体蛋白复合物的激活和共定位，并且在PA刺激后，大多数复合物与KC的线粒体共定位。综上所述，我们的新发现表明，TXNIP通过结合并抑制NLRP3在NAFLD的发展中发挥保护和抗炎作用。
