A glucose-responsive transcription factor that regulates carbohydrate metabolism in the liver
A glucose-responsive transcription factor that regulates carbohydrate metabolism in the liver
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DOI：
10.1073/pnas.161284298
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发表时间：
2001-07-31
影响因子：
11.1
通讯作者：
Uyeda, K
中科院分区：
文献类型：
--
作者：
Yamashita, H;Takenoshita, M;Uyeda, K
碳水化合物通过促进限速糖酵解酶和脂肪生成酶的快速翻译后激活以及编码许多这些相同酶的基因的转录诱导来介导其在肝脏中转化为甘油三酯。碳水化合物水平升高影响这些基因转录的机制仍然未知。在这里，我们报告的纯化和鉴定的转录因子，识别碳水化合物反应元件（ChRE）的启动子内的L型丙酮酸激酶（LPK）基因。大鼠肝脏中这种ChRE结合蛋白（ChREBP）的DNA结合活性是由高碳水化合物饮食特异性诱导的。ChREBP在体外的DNA结合特异性与体内启动子活性精确相关。此外，在原代肝细胞中，ChREBP的强制过表达激活了L型丙酮酸激酶启动子的转录，以响应高葡萄糖水平。ChREBP的DNA结合活性可以通过其磷酸化状态的变化在体外进行调节，这表明葡萄糖响应调节的可能模式。ChREBP可能对于过量碳水化合物作为脂肪的最佳长期储存至关重要，并且可能导致营养利用和肥胖症特征储存之间的不平衡。
Carbohydrates mediate their conversion to triglycerides in the liver by promoting both rapid posttranslational activation of rate-limiting glycolytic and lipogenic enzymes and transcriptional induction of the genes encoding many of these same enzymes. The mechanism by which elevated carbohydrate levels affect transcription of these genes remains unknown. Here we report the purification and identification of a transcription factor that recognizes the carbohydrate response element (ChRE} within the promoter of the L-type pyruvate kinase (LPK} gene. The DNA-binding activity of this ChRE-binding protein (ChREBP} in rat fivers is specifically induced by a high carbohydrate diet. ChREBP's DNA-binding specificity in vitro precisely correlates with promoter activity in vivo. Furthermore, forced ChREBP overexpression in primary hepatocytes activates transcription from the L-type Pyruvate kinase promoter in response to high glucose levels. The DNA-binding activity of ChREBP can be modulated in vitro by means of changes in its phosphorylation state, suggesting a possible mode of glucose-responsive regulation. ChREBP is likely critical for the optimal long-term storage of excess carbohydrates as fats, and may contribute to the imbalance between nutrient utilization and storage characteristic of obesity.