College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Korea; Department of Pharmacology, School of Medicine, Wonkwang University, Iksan, Jeonbuk 54538, Korea.
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Korea.
Cell Rep. 2018 Sep 11;24(11):2985-2999. doi: 10.1016/j.celrep.2018.07.068.
Endoplasmic reticulum (ER) stress is associated with liver injury and fibrosis, and yet the hepatic factors that regulate ER stress-mediated inflammasome activation remain unknown. Here, we report that farnesoid X receptor (FXR) activation inhibits ER stress-induced NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome in hepatocytes. In patients with hepatitis B virus (HBV)-associated hepatic failure or non-alcoholic fatty liver disease, and in mice with liver injury, FXR levels in the liver inversely correlated with the extent of NLRP3 inflammasome activation. Fxr deficiency in mice augmented the ability of ER stress to induce NLRP3 and thioredoxin-interacting protein (TXNIP), whereas FXR ligand activation prevented it, ameliorating liver injury. FXR attenuates CCAAT-enhancer-binding protein homologous protein (CHOP)-dependent NLRP3 overexpression by inhibiting ER stress-mediated protein kinase RNA-like endoplasmic reticulum kinase (PERK) activation. Our findings implicate miR-186 and its target, non-catalytic region of tyrosine kinase adaptor protein 1 (NCK1), in mediating the inhibition of ER stress by FXR. This study provides the insights on how FXR regulation of ER stress ameliorates hepatocyte death and liver injury and on the molecular basis of NLRP3 inflammasome activation.
内质网（ER）应激与肝损伤和纤维化有关，但调节 ER 应激介导的炎症小体激活的肝内因素尚不清楚。在这里，我们报告法尼醇 X 受体（FXR）的激活可抑制肝实质细胞中 ER 应激诱导的 NACHT、LRR 和 PYD 结构域包含蛋白 3（NLRP3）炎症小体。在乙型肝炎病毒（HBV）相关肝衰竭或非酒精性脂肪性肝病患者和肝损伤的小鼠中，FXR 在肝脏中的水平与 NLRP3 炎症小体激活的程度呈负相关。在 Fxr 敲除小鼠中，内质网应激诱导 NLRP3 和硫氧还蛋白相互作用蛋白（TXNIP）的能力增强，而 FXR 配体的激活则阻止了这一过程，从而改善了肝损伤。FXR 通过抑制 ER 应激介导的蛋白激酶 RNA 样内质网激酶（PERK）激活，减弱 CCAAT 增强子结合蛋白同源蛋白（CHOP）依赖性 NLRP3 的过表达。我们的研究结果表明，miR-186 及其靶基因酪氨酸激酶衔接蛋白 1 的非催化区（NCK1），在介导 FXR 对 ER 应激的抑制中起作用。这项研究提供了关于 FXR 如何调节 ER 应激来减轻肝实质细胞死亡和肝损伤以及 NLRP3 炎症小体激活的分子基础的见解。
