ADD1/SREBP1 promotes adipocyte differentiation and gene expression linked to fatty acid metabolism
ADD1/SREBP1 promotes adipocyte differentiation and gene expression linked to fatty acid metabolism
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DOI：
10.1101/gad.10.9.1096
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发表时间：
1996-05-01
影响因子：
10.5
通讯作者：
Spiegelman, BM
中科院分区：
文献类型：
--
作者：
Kim, JB;Spiegelman, BM
脂肪细胞决定和分化依赖因子1（ADD 1）是碱性螺旋-环-螺旋亮氨酸拉链（bHLH-LZ）转录因子家族的成员，其结合两种不同的DNA。序列，并已与脂肪细胞发育和胆固醇稳态（其中它已被称为SREBP 1）。为了研究ADD 1的生物学作用，我们在前脂肪细胞和非脂肪细胞中用逆转录病毒载体表达了该蛋白的野生型和显性阴性形式。在DNA结合域中具有点突变的显性阴性形式的ADD 1急剧抑制3 T3-L1细胞的分化，如形态学上或通过脂肪细胞特异性mRNA的表达所观察到的。当异位表达ADD 1的NIH-3 T3细胞在不利于分化的激素条件下培养时，它们不会明显分化，但仍然激活脂肪酸合成酶（FAS）和脂蛋白脂酶（LPL）的mRNA表达，这两个基因调节脂肪酸代谢。在允许分化的包括PPAR激活剂的培养条件下，15%-20%的表达ADD 1的细胞经历脂肪形成，而2%-3%的含有对照载体的细胞分化。ADD 1与PPAR γ的同时表达增加了这种成脂核激素受体的转录活性，表明ADD 1参与了这一途径。这些数据表明，ADD 1在脂肪细胞基因表达和分化中起着重要作用，并表明它可能通过增加PPAR γ介导的转录中的一个步骤来发挥作用。
Adipocyte determination and differentiation-dependent factor 1 (ADD1) is a member of the basic helix-loop-helix leucine zipper (bHLH-LZ) family of transcription factors that binds to two distinct DNA. sequences and has been associated with both adipocyte development and cholesterol homeostasis (where it has been termed SREBP1). To investigate the biological role of ADD1, we expressed wild-type and dominant negative forms of this protein with retroviral vectors in preadipocytes and nonadipogenic cells. A dominant-negative form of ADD1 with a point mutation in the DNA-binding domain sharply represses the differentiation of 3T3-L1 cells as observed morphologically or by the expression of adipocyte-specific mRNAs. When NIH-3T3 cells ectopically expressing ADD1 are cultured under hormonal conditions not favoring differentiation, they do not overtly differentiate but still activate expression of mRNAs for fatty acid synthase (FAS) and lipoprotein lipase (LPL), two key genes that regulate fatty acid metabolism. Under culture conditions permissive for differentiation including a PPAR activator, 15%-20% of the cells expressing ADD1 undergo adipogenesis while 2%-3% of cells containing a control vector differentiate. Simultaneous expression of ADD1 with PPAR gamma increases the transcriptional activity of this adipogenic nuclear hormone receptor, suggesting involvement of ADD1 in this pathway. These data indicate that ADD1 plays an important role in fat cell gene expression and differentiation, and suggest that it may function by augmenting a step in PPAR gamma-mediated transcription.