Coordinated control of cholesterol catabolism to bile acids and of gluconeogenesis via a novel mechanism of transcription regulation linked to the fasted-to-fed cycle
Coordinated control of cholesterol catabolism to bile acids and of gluconeogenesis via a novel mechanism of transcription regulation linked to the fasted-to-fed cycle
复制标题
DOI：
10.1074/jbc.m305079200
复制
发表时间：
2003-10-03
影响因子：
4.8
通讯作者：
Crestani, M
中科院分区：
文献类型：
--
作者：
De Fabiani, E;Mitro, N;Crestani, M
胆汁酸代谢在胆固醇稳态中起重要作用，并且对于动脉粥样硬化疾病的发生至关重要。然而，尽管最近的进展，胆汁酸调节基因转录和胆固醇稳态在哺乳动物的分子机制仍然需要进一步的调查。在这里，我们表明，胆汁酸抑制基因（CYP 7A 1）编码胆固醇7 α-羟化酶，在胆汁酸生物合成的限速酶的转录，也通过一个不寻常的机制，不涉及胆汁酸核受体，法尼醇X受体。通过进行基于细胞的报告分析，蛋白质/蛋白质相互作用，染色质免疫沉淀分析，我们证明胆汁酸损害招聘过氧化物酶体增殖物激活受体-γ辅激活因子-1 α和cAMP反应元件结合蛋白结合蛋白的肝细胞核因子-4 α，CYP 7A 1的主调节。我们还首次表明，胆汁酸通过相同的法尼醇X受体独立机制抑制编码磷酸烯醇丙酮酸羧激酶的基因（PEPCK）的转录，磷酸烯醇丙酮酸羧激酶是胚胎发生中的限速酶。染色质免疫沉淀分析显示，胆汁酸诱导的肝细胞核因子-4 α共激活因子的解离减少了RNA聚合酶II在这两个基因的核心启动子和3 '非翻译区下游的募集，反映了基因转录的减少。最后，我们发现Cyp 7a 1的表达在禁食小鼠中与Pepck平行地被刺激，而相同的基因被胆汁酸抑制。总的来说，这些结果揭示了一种新的调控机制，控制基因转录响应细胞外刺激，并认为，转录调控胆汁酸的胆固醇和葡萄糖代谢的核心基因，应动态地看待的背景下，禁食到进食周期。
Bile acid metabolism plays an essential role in cholesterol homeostasis and is critical for the initiation of atherosclerotic disease. However, despite the recent advances, the molecular mechanisms whereby bile acids regulate gene transcription and cholesterol homeostasis in mammals still need further investigations. Here, we show that bile acids suppress transcription of the gene (CYP7A1) encoding cholesterol 7alpha-hydroxylase, the rate-limiting enzyme in bile acid biosynthesis, also through an unusual mechanism not involving the bile acid nuclear receptor, farnesoid X receptor. By performing cell-based reporter assays, protein/protein interaction, and chromatin immunoprecipitation assays, we demonstrate that bile acids impair the recruitment of peroxisome proliferator-activated receptor-gamma coactivator-1alpha and cAMP response element-binding protein-binding protein by hepatocyte nuclear factor-4alpha, a master regulator of CYP7A1. We also show for the first time that bile acids inhibit transcription of the gene ( PEPCK) encoding phosphoenolpyruvate carboxykinase, the rate-limiting enzyme in gluconeogenesis, through the same farnesoid X receptor-independent mechanism. Chromatin immunoprecipitation assay revealed that bile acid-induced dissociation of coactivators from hepatocyte nuclear factor-4alpha decreased the recruitment of RNA polymerase II to the core promoter and downstream in the 3'-untranslated regions of these two genes, reflecting the reduction of gene transcription. Finally, we found that Cyp7a1 expression was stimulated in fasted mice in parallel to Pepck, whereas the same genes were repressed by bile acids. Collectively, these results reveal a novel regulatory mechanism that controls gene transcription in response to extracellular stimuli and argue that the transcription regulation by bile acids of genes central to cholesterol and glucose metabolism should be viewed dynamically in the context of the fasted-to-fed cycle.