Lipotoxicity leads to numerous metabolic disorders such as nonalcoholic steatohepatitis. Luteolin, apigenin, and chrysin are three flavones with known antioxidant and anti‐inflammatory properties, but whether they inhibit lipotoxicity‐mediated NLRP3 inflammasome activation was unclear. To address this question, we used J774A.1 macrophages and Kupffer cells stimulated with 100 μM palmitate (PA) in the presence or absence of 20 μM of each flavone. PA increased p‐PERK, p‐IRE1α, p‐JNK1/2, CHOP, and TXNIP as well as p62 and LC3‐II expression and induced autophagic flux damage. Caspase‐1 activation and IL‐1β release were also noted after 24 h of exposure to PA. In the presence of the PERK inhibitor GSK2656157, PA‐induced CHOP and TXNIP expression and caspase‐1 activation were mitigated. Compared with PA treatment alone, Bcl‐2 coupled to beclin‐1 was elevated and autophagy was reversed by the JNK inhibitor SP600125. With luteolin, apigenin, and chrysin treatment, PA‐induced ROS production, ER stress, TXNIP expression, autophagic flux damage, and apoptosis were ameliorated. Moreover, TXNIP binding to NLRP3 and IL‐1β release in response to LPS/PA challenge were reduced. These results suggest that luteolin, apigenin, and chrysin protect hepatic macrophages against PA‐induced NLRP3 inflammasome activation and autophagy damage by attenuating endoplasmic reticulum stress.

中文翻译：

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木犀草素、芹菜素和白杨素通过抑制内质网应激来抑制巨噬细胞中脂毒性诱导的 NLRP3 炎症小体激活和自噬损伤

脂毒性导致许多代谢紊乱，例如非酒精性脂肪性肝炎。木犀草素、芹菜素和白杨素是三种已知具有抗氧化和抗炎特性的黄酮，但它们是否抑制脂毒性介导的 NLRP3 炎症小体激活尚不清楚。为了解决这个问题，我们使用了在存在或不存在 20 μM 每种黄酮的情况下用 100 μM 棕榈酸酯 (PA) 刺激的 J774A.1 巨噬细胞和 Kupffer 细胞。 PA 增加 p-PERK、p-IRE1α、p-JNK1/2、CHOP 和 TXNIP 以及 p62 和 LC3-II 的表达，并诱导自噬流损伤。暴露于 PA 24 小时后还注意到 Caspase-1 激活和 IL-1β 释放。在 PERK 抑制剂 GSK2656157 存在的情况下，PA 诱导的 CHOP 和 TXNIP 表达以及 caspase-1 激活得到减轻。与单独的 PA 治疗相比，与 beclin-1 偶联的 Bcl-2 升高，JNK 抑制剂 SP600125 逆转自噬。通过木犀草素、芹菜素和白杨素治疗，PA 诱导的 ROS 产生、ER 应激、TXNIP 表达、自噬流损伤和细胞凋亡得到改善。此外，响应 LPS/PA 攻击的 TXNIP 与 NLRP3 的结合和 IL-1β 的释放减少。这些结果表明，木犀草素、芹菜素和白杨素通过减弱内质网应激，保护肝巨噬细胞免受 PA 诱导的 NLRP3 炎性体激活和自噬损伤。