Sha Haibo, He Yin, Chen Hui, Wang Cindy, Zenno Anna, Shi Hang, Yang Xiaoyong, Zhang Xinmin, Qi Ling
Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.
Cell Metab. 2009 Jun;9(6):556-64. doi: 10.1016/j.cmet.2009.04.009.
Signaling cascades during adipogenesis culminate in the expression of two essential adipogenic factors, PPARgamma and C/EBPalpha. Here we demonstrate that the IRE1alpha-XBP1 pathway, the most conserved branch of the unfolded protein response (UPR), is indispensable for adipogenesis. Indeed, XBP1-deficient mouse embryonic fibroblasts and 3T3-L1 cells with XBP1 or IRE1alpha knockdown exhibit profound defects in adipogenesis. Intriguingly, C/EBPbeta, a key early adipogenic factor, induces Xbp1 expression by directly binding to its proximal promoter region. Subsequently, XBP1 binds to the promoter of Cebpa and activates its gene expression. The posttranscriptional splicing of Xbp1 mRNA by IRE1alpha is required as only the spliced form of XBP1 (XBP1s) rescues the adipogenic defect exhibited by XBP1-deficient cells. Taken together, our data show that the IRE1alpha-XBP1 pathway plays a key role in adipocyte differentiation by acting as a critical regulator of the morphological and functional transformations during adipogenesis.
脂肪生成过程中的信号级联反应最终导致两种重要的脂肪生成因子PPARγ和C/EBPα的表达。在此，我们证明IRE1α-XBP1通路，即未折叠蛋白反应（UPR）中最保守的分支，对脂肪生成不可或缺。事实上，XBP1缺陷的小鼠胚胎成纤维细胞以及敲低XBP1或IRE1α的3T3-L1细胞在脂肪生成方面表现出严重缺陷。有趣的是，关键的早期脂肪生成因子C/EBPβ通过直接结合其近端启动子区域来诱导Xbp1表达。随后，XBP1结合Cebpa的启动子并激活其基因表达。IRE1α对Xbp1 mRNA的转录后剪接是必需的，因为只有剪接形式的XBP1（XBP1s）才能挽救XBP1缺陷细胞所表现出的脂肪生成缺陷。综上所述，我们的数据表明，IRE1α-XBP1通路通过作为脂肪生成过程中形态和功能转变的关键调节因子，在脂肪细胞分化中发挥关键作用。
