Retinoic acid receptor-related orphan receptor stimulates adipose tissue inflammation by modulating endoplasmic reticulum stress
Retinoic acid receptor-related orphan receptor stimulates adipose tissue inflammation by modulating endoplasmic reticulum stress
复制标题
视黄酸受体相关孤儿受体通过调节内质网应激刺激脂肪组织炎症
DOI：
10.1074/jbc.m117.782391
复制
发表时间：
2017-08-25
影响因子：
4.8
通讯作者：
Su, Zhiguang
中科院分区：
文献类型：
--
作者：
Liu, Yin;Chen, Yulong;Su, Zhiguang
脂肪组织炎症与代谢疾病如肥胖和2型糖尿病有关。然而，介导脂肪组织炎症的分子尚未得到解决。虽然已知维甲酸受体相关孤儿受体（retinoic acid receptor- associated orphan receptor， ROR）在一些组织中参与炎症反应的调节，但其在脂肪组织中的作用在很大程度上是未知的。相反，已知内质网（ER）应激和展开蛋白反应（UPR）信号影响肥胖脂肪组织的炎症反应，但ROR是否调节这些过程仍不清楚。在这项研究中，我们研究了ROR和脂肪组织炎症之间的联系。我们发现脂多糖刺激巨噬细胞或3T3-L1脂肪细胞以及肥胖小鼠脂肪组织的炎症反应显著增加ROR的表达。腺病毒介导的ROR过表达或ROR特异性激动剂SR1078治疗可增强炎症细胞因子的表达，增加脂肪组织中浸润的巨噬细胞的数量。此外，SR1078上调内质网应激反应基因的mRNA表达，并增强了三种主要UPR信号通路中两种介质PERK和IRE1的磷酸化。最后，我们发现使用化学伴侣缓解内质网应激，随后抑制脂肪组织中ROR诱导的炎症。我们的数据表明，ror诱导的内质网应激反应可能会导致脂肪组织炎症，而这种炎症可以通过化学伴侣治疗来缓解。本文建立的ROR表达、炎症和UPR信号传导之间的关系可能对肥胖相关代谢疾病的治疗靶向具有启示意义。
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 (ROR) 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 ROR regulates these processes remains unknown. In this study, we investigate the link between ROR 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 ROR. Adenovirus-mediated overexpression of ROR or treatment with the ROR-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 IRE1. Finally, we found that alleviation of ER stress using a chemical chaperone followed by the suppression of ROR induced inflammation in adipose tissue. Our data suggest that ROR-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 ROR expression, inflammation, and UPR signaling may have implications for therapeutic targeting of obesity-related metabolic diseases.