Liu Yin, Chen Yulong, Zhang Jinlong, Liu Yulan, Zhang Yanjie, Su Zhiguang
From the Molecular Medicine Research Center, West China Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, Sichuan, China.
From the Molecular Medicine Research Center, West China Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, Sichuan, China.
J Biol Chem. 2017 Aug 25;292(34):13959-13969. doi: 10.1074/jbc.M117.782391. Epub 2017 Jul 11.
Adipose tissue inflammation has been linked to metabolic diseases such as obesity and type 2 diabetes. However, the molecules that mediate inflammation in adipose tissue have not been addressed. Although retinoic acid receptor-related orphan receptor α (RORα) is known to be involved in the regulation of inflammatory response in some tissues, its role is largely unknown in adipose tissue. Conversely, it is known that endoplasmic reticulum (ER) stress and unfolding protein response (UPR) signaling affect the inflammatory response in obese adipose tissue, but whether RORα regulates these processes remains unknown. In this study, we investigate the link between RORα and adipose tissue inflammation. We showed that the inflammatory response in macrophages or 3T3-L1 adipocytes stimulated by lipopolysaccharide, as well as adipose tissue in obese mice, markedly increased the expression of RORα. Adenovirus-mediated overexpression of RORα or treatment with the RORα-specific agonist SR1078 enhanced the expression of inflammatory cytokines and increased the number of infiltrated macrophages into adipose tissue. Furthermore, SR1078 up-regulated the mRNA expression of ER stress response genes and enhanced phosphorylations of two of the three mediators of major UPR signaling pathways, PERK and IRE1α. Finally, we found that alleviation of ER stress using a chemical chaperone followed by the suppression of RORα induced inflammation in adipose tissue. Our data suggest that RORα-induced ER stress response potentially contributes to the adipose tissue inflammation that can be mitigated by treatment with chemical chaperones. The relationships established here between RORα expression, inflammation, and UPR signaling may have implications for therapeutic targeting of obesity-related metabolic diseases.
脂肪组织炎症与肥胖和2型糖尿病等代谢性疾病有关。然而，介导脂肪组织炎症的分子尚未得到研究。尽管已知维甲酸受体相关孤儿受体α（RORα）参与某些组织中炎症反应的调节，但其在脂肪组织中的作用在很大程度上尚不清楚。相反，已知内质网（ER）应激和未折叠蛋白反应（UPR）信号会影响肥胖脂肪组织中的炎症反应，但RORα是否调节这些过程仍不清楚。在本研究中，我们调查了RORα与脂肪组织炎症之间的联系。我们发现，脂多糖刺激的巨噬细胞或3T3-L1脂肪细胞中的炎症反应，以及肥胖小鼠的脂肪组织，均显著增加了RORα的表达。腺病毒介导的RORα过表达或用RORα特异性激动剂SR1078处理可增强炎症细胞因子的表达，并增加浸润到脂肪组织中的巨噬细胞数量。此外，SR1078上调了ER应激反应基因的mRNA表达，并增强了主要UPR信号通路的三种介质中的两种，即PERK和IRE1α的磷酸化。最后，我们发现使用化学伴侣减轻ER应激，随后抑制RORα可诱导脂肪组织炎症。我们的数据表明，RORα诱导的ER应激反应可能导致脂肪组织炎症，而化学伴侣治疗可减轻这种炎症。这里建立的RORα表达、炎症和UPR信号之间的关系可能对肥胖相关代谢疾病的治疗靶点有影响。
