Covalent inhibition of endoplasmic reticulum chaperone GRP78 disconnects the transduction of ER stress signals to inflammation and lipid accumulation in diet-induced obese mice.
Covalent inhibition of endoplasmic reticulum chaperone GRP78 disconnects the transduction of ER stress signals to inflammation and lipid accumulation in diet-induced obese mice.
复制标题
内质网伴侣 GRP78 的共价抑制会断开饮食诱导的肥胖小鼠中内质网应激信号向炎症和脂质积累的转导。
作者：
Luo D;Fan N;Zhang X;Ngo FY;Zhao J;Zhao W;Huang M;Li D;Wang Y;Rong J
靶向内质网（ER）应激、炎症和代谢功能障碍可能会阻止肥胖的发病机制，从而降低糖尿病、心血管疾病和癌症的患病率。本研究旨在阐明植物源性雷公藤红素改善肥胖症炎症和脂质积聚的机制。通过高脂饲料喂养3个月诱导饮食诱导的肥胖小鼠模型，随后用雷公藤红素干预21天。分析肝脏和脂肪组织的脂质蓄积、巨噬细胞活化和生物标志物表达。结果，雷公藤红素有效地减轻体重，抑制ER应激、炎症和脂肪生成，同时促进肝脏脂肪分解。RNA测序显示，载雷公藤红素的纳米胶束恢复了49个调节ER应激、炎症和脂质代谢的基因的表达。另一方面，合成雷公藤红素-PEG 4-炔用于鉴定RAW 264.7巨噬细胞中的雷公藤红素结合蛋白。内质网伴侣GRP 78（78 kDa的葡萄糖调节蛋白）通过蛋白质组学方法鉴定雷公藤红素结合残基Cys 41。在结合和缀合后，雷公藤红素将GRP 78的伴侣活性降低了130倍，并降低了棕榈酸酯攻击细胞中的ER应激，而缺乏醌甲基化物的雷公藤红素类似物未能表现出抗肥胖作用。因此，共价GRP 78抑制可以诱导ER信号传导、炎症和代谢的重编程以对抗饮食诱导的肥胖。
Targeting endoplasmic reticulum (ER) stress, inflammation, and metabolic dysfunctions may halt the pathogenesis of obesity and thereby reduce the prevalence of diabetes, cardiovascular disesases, and cancers. The present study was designed to elucidate the mechnaisms by which plant-derived celastrol ameliorated inflammation and lipid accumulation in obesity. The mouse model of diet-induced obesity was induced by feeding high-fat diet for 3 months and subsequently intervented with celastrol for 21 days. Hepatic and adipose tissues were analyzed for lipid accumulation, macrophage activation, and biomarker expression. As result, celastrol effectively reduced body weight, suppressed ER stress, inflammation, and lipogenesis while promoted hepatic lipolysis. RNA-sequencing revealed that celastrol-loaded nanomicelles restored the expression of 49 genes that regulate ER stress, inflammation, and lipid metabolism. On the other hand, celastrol-PEG4-alkyne was synthesized for identifying celastrol-bound proteins in RAW264.7 macrophages. ER chaperone GRP78 (78 kDa glucose-regulated protein) was identified by proteomics approach for celastrol binding to the residue Cys41. Upon binding and conjugation, celastrol diminished the chaperone activity of GRP78 by 130-fold and reduced ER stress in palmitate-challenged cells, while celastrol analog lacking quinone methide failed to exhibit antiobesity effects. Thus, covalent GRP78 inhibition may induce the reprograming of ER signaling, inflammation, and metabolism against diet-induced obesity.