Ajuba functions as a co-activator of C/EBPβ to induce expression of PPARγ and C/EBPα during adipogenesis
Ajuba functions as a co-activator of C/EBPβ to induce expression of PPARγ and C/EBPα during adipogenesis
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DOI：
10.1016/j.mce.2021.111485
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发表时间：
2021-10
影响因子：
4.1
通讯作者：
Han Yan;Qi Li;Mengying Li;X. Zou;N. Bai;Zichao Yu;Jie Zhang;Dan Zhang;Qun Zhang;Jiamin Wang;Hao Jia;Yingjie Wu;Z. Hou
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文献类型：
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作者：
Han Yan;Qi Li;Mengying Li;X. Zou;N. Bai;Zichao Yu;Jie Zhang;Dan Zhang;Qun Zhang;Jiamin Wang;Hao Jia;Yingjie Wu;Z. Hou
脂肪形成受一个复杂的转录因子网络调控，其中PPARγ和C/EBP家族成员是主要的调控因子。在脂肪形成过程中，C/EBPβ在早期被诱导，然后反式激活PPARγ和C/EBPα，其协同诱导基因的表达产生成熟脂肪细胞表型。确定影响C/EBPβ表达和活性的因素应该为调节脂肪形成的机制提供额外的见解。在这里，我们证明，在3 T3-L1细胞中，Ajuba的耗竭显著降低了PPARγ和C/EBPα的mRNA和蛋白水平，损害了脂肪细胞分化，而过表达增加了这些基因的表达，促进了脂肪细胞分化。此外，在Ajuba缺陷的3 T3-L1细胞中，C/EBPα或PPARγ表达的恢复改善了受损的脂质积累。在机制上，筋骨草与C/EBPβ相互作用并募集CBP，以促进C/EBPβ与PPARγ和C/EBPα的启动子结合，导致H3组蛋白乙酰化和靶基因表达增加。总之，这些数据表明，Ajuba作为C/EBPβ的共激活剂发挥作用，可能是对抗肥胖相关疾病的重要治疗靶点。
Adipogenesis is regulated by a complicated network of transcription factors among which PPARγ and C/EBP family members are the major regulators. During adipogenesis, C/EBPβ is induced early and then transactivates PPARγ and C/EBPα, which cooperatively induce genes whose expressions give rise to the mature adipocyte phenotype. Identifying the factors that influence the expression and activity of C/EBPβ should provide additional insight into the mechanisms regulating adipogenesis. Here, we demonstrate that depletion of Ajuba in 3T3-L1 cells significantly decreases mRNA and protein levels of PPARγ and C/EBPα and impairs adipocyte differentiation, while overexpression increases expression of these genes and promotes adipocyte differentiation. Moreover, restoration of C/EBPα or PPARγ expression in Ajuba-deficient 3T3-L1 cells improves the impaired lipid accumulation. Mechanistically, Ajuba interacts with C/EBPβ and recruits CBP to facilitate the binding of C/EBPβ to the promoter of PPARγ and C/EBPα, resulting in increased H3 histone acetylation and target gene expression. Collectively, these data indicate that Ajuba functions as a co-activator of C/EBPβ, and may be an important therapeutic target for combating obesity-related diseases.