Hallett Center for Diabetes and Endocrinology, Department of Medicine, Brown Medical School, Providence, Rhode Island, USA.
Obesity (Silver Spring). 2011 Mar;19(3):483-91. doi: 10.1038/oby.2010.200. Epub 2010 Sep 9.
Free-fatty acids (FFAs) are well-characterized factor for causing production of inflammatory factors and insulin resistance in adipocytes. Using cultured adipocytes, we demonstrate that FFAs can activate endoplasmic reticulum (ER) stress pathway by examination of ER stress sensor activation and marker gene expression. Chemical chaperone tauroursodeoxycholic acid (TUDCA) can reduce FFA-induced adipocyte inflammation and improve insulin signaling whereas overexpression of spliced X-box protein 1 (XBP-1s) only attenuates FFA-induced inflammation. PKR-like eukaryotic initiation factor 2α kinase (PERK) is one of the three major ER stress sensor proteins and deficiency of PERK alleviates FFA-induced inflammation and insulin resistance. The key downstream target of FFA-induced ER stress is IκB kinase β (IKKβ), a master kinase for regulating expression of inflammatory genes. Deficiency of PERK attenuates FFA-induced activation of IKKβ and deficiency of IKKβ alleviates FFA-induced inflammation and insulin resistance. Consistently, overexpression of IKKβ in 3T3-L1 CAR adipocytes causes inflammation and insulin resistance. In addition, IKKβ overexpression has profound effect on adipocyte lipid metabolism, including inhibition of lipogenesis and promotion of lipolysis. Furthermore, increased endogenous IKKβ expression and activation is also observed in isolated primary adipocytes from mice injected with lipids or fed on high-fat diet (HFD) acutely. These results indicate that ER stress pathway is a key mediator for FFA-induced inflammation and insulin resistance in adipocytes with PERK and IKKβ as the critical signaling components.
游离脂肪酸（FFAs）是引起脂肪细胞产生炎症因子和胰岛素抵抗的特征因子。通过培养的脂肪细胞实验，我们发现 FFAs 通过内质网（ER）应激传感器的激活和标记基因的表达，激活 ER 应激途径。化学伴侣熊去氧胆酸（TUDCA）可以减少 FFA 诱导的脂肪细胞炎症并改善胰岛素信号，而剪接 X 盒蛋白 1（XBP-1s）的过表达仅能减轻 FFA 诱导的炎症。PKR 样真核起始因子 2α 激酶（PERK）是 ER 应激传感器蛋白的三种主要蛋白之一，PERK 的缺乏减轻了 FFA 诱导的炎症和胰岛素抵抗。FFA 诱导的 ER 应激的关键下游靶标是 IκB 激酶β（IKKβ），它是调节炎症基因表达的主要激酶。PERK 的缺乏减轻了 FFA 诱导的 IKKβ的激活，而 IKKβ的缺乏减轻了 FFA 诱导的炎症和胰岛素抵抗。同样，3T3-L1 CAR 脂肪细胞中 IKKβ的过表达会引起炎症和胰岛素抵抗。此外，IKKβ的过表达对脂肪细胞脂质代谢有深远影响，包括抑制脂肪生成和促进脂肪分解。此外，在注射脂质或高脂饮食（HFD）的小鼠分离的原代脂肪细胞中，也观察到内源性 IKKβ表达和激活增加。这些结果表明，在脂肪细胞中，内质网应激途径是 FFA 诱导的炎症和胰岛素抵抗的关键介质，PERK 和 IKKβ是关键的信号成分。
