Kim J B, Wright H M, Wright M, Spiegelman B M
Dana-Farber Cancer Institute and the Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4333-7. doi: 10.1073/pnas.95.8.4333.
Adipose differentiation is an important part of the energy homeostasis system of higher organisms. Recent data have suggested that this process is controlled by an interplay of transcription factors including PPARgamma, the C/EBPs, and ADD1/SREBP1. Although these factors interact functionally to initiate the program of differentiation, there are no data concerning specific mechanisms of interaction. We show here that the expression of ADD1/SREBP1 specifically increases the activity of PPARgamma but not other isoforms, PPARalpha, or PPARdelta. This activation occurs through the ligand-binding domain of PPARgamma when it is fused to the DNA-binding domain of Gal4. The stimulation of PPARgamma by ADD1/SREBP1 does not require coexpression in the same cells; supernatants from cultures that express ADD1/SREBP1 augment the transcriptional activity of PPARgamma. Finally, we demonstrate directly that cells expressing ADD1/SREBP1 produce and secrete lipid molecule(s) that bind directly to PPARgamma, displacing the binding of radioactive thiazolidinedione ligands. These data establish that ADD1/SREBP1 can control the production of endogenous ligand(s) for PPARgamma and suggest a mechanism for coordinating the actions of these adipogenic factors.
脂肪分化是高等生物能量稳态系统的重要组成部分。最近的数据表明，这一过程受包括PPARγ、C/EBP家族以及ADD1/SREBP1在内的转录因子相互作用的控制。尽管这些因子在功能上相互作用以启动分化程序，但尚无关于具体相互作用机制的数据。我们在此表明，ADD1/SREBP1的表达特异性地增加了PPARγ的活性，而不影响其他亚型，如PPARα或PPARδ。当PPARγ的配体结合结构域与Gal4的DNA结合结构域融合时，这种激活通过PPARγ的配体结合结构域发生。ADD1/SREBP1对PPARγ的刺激不需要在同一细胞中共表达；表达ADD1/SREBP1的培养上清液增强了PPARγ的转录活性。最后，我们直接证明，表达ADD1/SREBP1的细胞产生并分泌直接与PPARγ结合的脂质分子，取代放射性噻唑烷二酮配体的结合。这些数据表明，ADD1/SREBP可以控制PPARγ内源性配体的产生，并提示了一种协调这些脂肪生成因子作用的机制。
