Fatty acid and endotoxin activate inflammasomes in mouse hepatocytes that release danger signals to stimulate immune cells.
Fatty acid and endotoxin activate inflammasomes in mouse hepatocytes that release danger signals to stimulate immune cells.
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DOI：
10.1002/hep.24341
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发表时间：
2011-07
期刊：
影响因子：
13.5
通讯作者：
Szabo, Gyongyi
中科院分区：
文献类型：
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作者：
Csak, Timea;Ganz, Michal;Pespisa, Justin;Kodys, Karen;Dolganiuc, Angela;Szabo, Gyongyi
非酒精性脂肪性肝炎（NASH）和炎性小体激活的发病机制涉及连续性打击。炎性小体在内源性和外源性危险信号的诱导下，将白细胞介素1β原（pro-IL-1β）裂解为分泌性IL-1β。脂多糖（LPS），一种toll样受体4配体，在NASH中起作用，也激活炎性小体。在这项研究中，我们假设炎症小体在NASH中被涉及内源性和外源性危险信号的多次击中激活。使用蛋氨酸胆碱缺乏（MCD）饮食诱导的NASH和高脂饮食诱导的NASH小鼠模型，我们发现炎性小体[包括NACHT、LRR和PYD结构域蛋白3]上调，（NALP 3; cryopyrin）、凋亡相关的含有斑点状CARD结构域的蛋白质、泛连接蛋白-1和胱天蛋白酶原-1]在信使RNA（mRNA）水平增加胱天蛋白酶-1活性，与对照肝脏相比，脂肪性肝炎小鼠中的成熟IL-1β蛋白水平。在仅有脂肪变性的小鼠中没有炎性小体活化。MCD饲料使小鼠对LPS诱导的肝脏中NALP 3、泛连接蛋白-1、IL-1β mRNA和成熟IL-1β蛋白水平升高敏感。我们首次证明了脂肪性肝炎中的离体肝细胞中存在炎性小体激活。我们的新数据表明，饱和脂肪酸（FA）棕榈酸（PA）激活炎性小体并诱导对LPS诱导的肝细胞中IL-1β释放的敏化。此外，PA以半胱天冬酶依赖性方式触发肝细胞释放危险信号。这些肝细胞来源的危险信号反过来又激活肝脏单核细胞中的炎性小体、IL-1β和肿瘤坏死因子α的释放。我们的新发现表明，饱和的FA以第一次打击的形式代表内源性危险，上调NASH中的炎性小体，并诱导对LPS的第二次打击的敏感性，以在肝细胞中释放IL-β。此外，暴露于饱和脂肪酸的肝细胞释放危险信号，触发免疫细胞中的炎性小体激活。因此，肝细胞在协调组织对NASH危险信号的反应中起关键作用。
The pathogenesis of nonalcoholic steatohepatitis (NASH) and inflammasome activation involves sequential hits. The inflammasome, which cleaves pro–interleukin-1β (pro–IL-1β) into secreted IL-1β, is induced by endogenous and exogenous danger signals. Lipo-polysaccharide (LPS), a toll-like receptor 4 ligand, plays a role in NASH and also activates the inflammasome. In this study, we hypothesized that the inflammasome is activated in NASH by multiple hits involving endogenous and exogenous danger signals. Using mouse models of methionine choline–deficient (MCD) diet–induced NASH and high-fat diet–induced NASH, we found up-regulation of the inflammasome [including NACHT, LRR, and PYD domains–containing protein 3 (NALP3; cryopyrin), apoptosis-associated specklike CARD-domain containing protein, pannexin-1, and pro–caspase-1] at the messenger RNA (mRNA) level increased caspase-1 activity, and mature IL-1β protein levels in mice with steatohepatitis in comparison with control livers. There was no inflammasome activation in mice with only steatosis. The MCD diet sensitized mice to LPS-induced increases in NALP3, pannexin-1, IL-1β mRNA, and mature IL-1β protein levels in the liver. We demonstrate for the first time that inflammasome activation occurs in isolated hepatocytes in steatohepatitis. Our novel data show that the saturated fatty acid (FA) palmitic acid (PA) activates the inflammasome and induces sensitization to LPS-induced IL-1β release in hepatocytes. Furthermore, PA triggers the release of danger signals from hepatocytes in a caspase-dependent manner. These hepatocyte-derived danger signals, in turn, activate inflammasome, IL-1β, and tumor necrosis factor α release in liver mononuclear cells. Our novel findings indicate that saturated FAs represent an endogenous danger in the form of a first hit, up-regulate the inflammasome in NASH, and induce sensitization to a second hit with LPS for IL-β release in hepatocytes. Furthermore, hepatocytes exposed to saturated FAs release danger signals that trigger inflammasome activation in immune cells. Thus, hepatocytes play a key role in orchestrating tissue responses to danger signals in NASH.
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影响因子：
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作者：
Neuschwander-Tetri, Brent A
通讯作者：
Neuschwander-Tetri, Brent A
影响因子：
7.7
作者：
Cani, Patrice D.;Amar, Jacques;Burcelin, Remy
通讯作者：
Burcelin, Remy
DOI：
10.1002/hep.22470
发表时间：
2008-10
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Hritz I;Mandrekar P;Velayudham A;Catalano D;Dolganiuc A;Kodys K;Kurt-Jones E;Szabo G
通讯作者：
Szabo G
影响因子：
3.7
作者：
Oosterveer MH;van Dijk TH;Tietge UJ;Boer T;Havinga R;Stellaard F;Groen AK;Kuipers F;Reijngoud DJ
通讯作者：
Reijngoud DJ
影响因子：
--
作者：
Cazanave SC;Gores GJ
通讯作者：
Gores GJ