Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Hepatology. 2011 Jul;54(1):133-44. doi: 10.1002/hep.24341.
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. Lipopolysaccharide (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 speck-like 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.
非酒精性脂肪性肝炎（NASH）的发病机制和炎性小体激活涉及连续打击。炎性小体通过内源性和外源性危险信号将前白细胞介素-1β（pro-IL-1β）切割成分泌型白细胞介素-1β（IL-1β），并被其诱导。脂多糖（LPS）是一种 Toll 样受体 4 配体，在 NASH 中起作用，也可激活炎性小体。在这项研究中，我们假设炎性小体通过涉及内源性和外源性危险信号的多种打击在 NASH 中被激活。我们使用蛋氨酸胆碱缺乏（MCD）饮食诱导的 NASH 模型和高脂肪饮食诱导的 NASH 模型，发现炎性小体[包括 NACHT、LRR 和 PYD 结构域包含蛋白 3（NALP3；冷诱导 RNA 结合蛋白）、凋亡相关斑点样含 CARD 结构域蛋白、连接蛋白-1 和前胱天蛋白酶-1]的信使 RNA（mRNA）水平上调，caspase-1 活性增加，以及成熟的白细胞介素-1β（IL-1β）蛋白水平在患有脂肪性肝炎的小鼠中与对照肝脏相比有所增加。仅患有脂肪变性的小鼠中没有炎性小体激活。MCD 饮食使小鼠对 LPS 诱导的 NALP3、连接蛋白-1、IL-1βmRNA 和成熟 IL-1β蛋白水平在肝脏中的增加敏感。我们首次证明炎性小体激活发生在脂肪性肝炎的分离肝细胞中。我们的新数据表明，饱和脂肪酸（FA）棕榈酸（PA）激活炎性小体，并诱导肝细胞对 LPS 诱导的 IL-1β释放产生敏感性。此外，PA 以胱天蛋白酶依赖性方式从肝细胞中释放危险信号。这些来自肝细胞的危险信号反过来又在肝单核细胞中激活炎性小体、IL-1β和肿瘤坏死因子-α的释放。
我们的新发现表明，饱和 FAs 以第一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 诱导的 IL-β释放的敏感性增加。此外，暴露于饱和 FAs 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 NASH 中组织对危险信号的反应中起关键作用。
