CREB controls hepatic lipid metabolism through nuclear hormone receptor PPAR-γ
CREB controls hepatic lipid metabolism through nuclear hormone receptor PPAR-γ
复制标题
DOI：
10.1038/nature02110
复制
发表时间：
2003-11-13
期刊：
影响因子：
64.8
通讯作者：
Montminy, M
中科院分区：
文献类型：
--
作者：
Herzig, S;Hedrick, S;Montminy, M
禁食触发了一系列激素信号，通过诱导肝脏中的葡萄糖输出和脂质分解来促进能量平衡（1）。cAMP反应性转录因子CREB通过刺激核激素受体辅激活因子PGC-1的表达，对胰高血糖素和肾上腺皮质醇做出反应，激活促血管生成和脂肪酸氧化程序（参考文献2-5）。同时，禁食也抑制脂质储存和合成（脂肪生成）途径（1），但其潜在机制尚不清楚。在这里，我们发现CREB活性缺陷的小鼠具有脂肪肝表型，并且显示核激素受体PPAR-gamma的表达升高，PPAR-gamma是脂肪生成基因的关键调节因子（6，7）。CREB通过刺激分裂毛状增强子（HES-1）基因的表达来抑制禁食状态下的肝PPAR-gamma表达，该基因是一种转录抑制物，在此显示为体内禁食脂质代谢的介体。协调诱导PGC-1和抑制PPAR-gamma的CREB在禁食期间提供了胰岛素和反调节激素之间的拮抗作用的分子原理，并表明CREB拮抗剂作为治疗剂在增强肝脏中的胰岛素敏感性的潜在作用。
Fasting triggers a series of hormonal cues that promote energy balance by inducing glucose output and lipid breakdown in the liver(1). In response to pancreatic glucagon and adrenal cortisol, the cAMP-responsive transcription factor CREB activates gluconeogenic and fatty acid oxidation programmes by stimulating expression of the nuclear hormone receptor coactivator PGC-1 (refs 2-5). In parallel, fasting also suppresses lipid storage and synthesis ( lipogenic) pathways(1), but the underlying mechanism is unknown. Here we show that mice deficient in CREB activity have a fatty liver phenotype and display elevated expression of the nuclear hormone receptor PPAR-gamma, a key regulator of lipogenic genes(6,7). CREB inhibits hepatic PPAR-gamma expression in the fasted state by stimulating the expression of the Hairy Enhancer of Split (HES-1) gene, a transcriptional repressor that is shown here to be a mediator of fasting lipid metabolism in vivo. The coordinate induction of PGC-1 and repression of PPAR-gamma by CREB during fasting provides a molecular rationale for the antagonism between insulin and counter-regulatory hormones, and indicates a potential role for CREB antagonists as therapeutic agents in enhancing insulin sensitivity in the liver.