Direct role of ChREBP•Mlx in regulating hepatic glucose-responsive genes
Direct role of ChREBP•Mlx in regulating hepatic glucose-responsive genes
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DOI：
10.1074/jbc.m413063200
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发表时间：
2005-03-25
影响因子：
4.8
通讯作者：
Towle, HC
中科院分区：
文献类型：
--
作者：
Ma, L;Tsatsos, NG;Towle, HC
哺乳动物在进食高碳水化合物食物后，肝脏中会诱导新生脂肪生成所需的酶。除了胰岛素外，葡萄糖代谢增加还会启动一条细胞内信号通路，从转录上调节编码产脂酶的基因。在其中几个基因的启动子区域发现了一个顺式作用序列，即碳水化合物反应元件(CHORE)。ChREBP(Carbon Response Element-Binding Protein)是近年来发现的葡萄糖信号转导途径中的一个候选转录因子。我们报道了ChREBP需要异二聚体伙伴最大样因子X(MLX)与Chore序列结合。在这项研究中，我们提供了进一步的证据来支持MLX在肝脏中的葡萄糖信号中的直接作用。我们构建了两种不同的显性负性MLX形式，它们可以与ChREBP二聚化，但阻止其与DNA的结合。当被引入肝细胞时，两种主要的阴性形式的MLX都抑制了含有Chore的转基因启动子的葡萄糖反应。加入外源野生型MLX或ChREBP可以挽救葡萄糖反应，但不能加入Mondoa，Mondoa是ChREBP的类似物，也可以与MLX形成异二聚体。此外，显性负MLX阻止了高糖条件下葡萄糖反应基因从其自然染色体环境中的诱导。相反，由胰岛素和甲状腺激素信号通路诱导的基因不受显性阴性MLX的影响。MLX存在于纯化ChREBP的肝核提取物的葡萄糖反应复合体中。综上所述，MLX是ChREBP在肝脏中调控成脂酶基因的必需伙伴。
Enzymes required for de novo lipogenesis are induced in mammalian liver after a meal high in carbohydrates. In addition to insulin, increased glucose metabolism initiates an intracellular signaling pathway that transcriptionally regulates genes encoding lipogenic enzymes. A cis-acting sequence, the carbohydrate response element (ChoRE), has been found in the promoter region of several of these genes. ChREBP (carbohydrate response element-binding protein) was recently identified as a candidate transcription factor in the glucose-signaling pathway. We reported that ChREBP requires the heterodimeric partner Max-like factor X (Mlx) to bind to ChoRE sequences. In this study we provide further evidence to support a direct role of Mlx in glucose signaling in the liver. We constructed two different dominant negative forms of Mlx that could dimerize with ChREBP but block its binding to DNA. When introduced into hepatocytes, both dominant negative forms of Mlx inhibited the glucose response of a transfected ChoRE-containing promoter. The glucose response was rescued by adding exogenous wild type Mlx or ChREBP, but not MondoA, a paralog of ChREBP that can also form a heterodimer with Mlx. Furthermore, dominant negative Mlx blocked the induction of glucose-responsive genes from their natural chromosomal context under high glucose conditions. In contrast, genes induced by the insulin and thyroid hormone-signaling pathways were unaffected by dominant negative Mlx. Mlx was present in the glucose-responsive complex of liver nuclear extract from which ChREBP was purified. In conclusion, Mlx is an obligatory partner of ChREBP in regulating lipogenic enzyme genes in liver.