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CREB controls hepatic lipid metabolism through nuclear hormone receptor PPAR-γ

机译:CREB通过核激素受体PPAR-γ控制肝脂质代谢

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Fasting triggers a series of hormonal cues that promote energy balance by inducing glucose output and lipid breakdown in the liver. In response to pancreatic glucagon and adrenal cortisol, the cAMP-responsive transcription factor CREB activates gluco-neogenic 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, 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-γ, a key regulator of lipogenic genes. CREB inhibits hepatic PPAR-γ 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-γ 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.
机译:空腹触发一系列激素信号,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。响应胰高血糖素和肾上腺皮质醇,cAMP响应转录因子CREB通过刺激核激素受体共激活因子PGC-1的表达来激活糖异生和脂肪酸氧化程序(参考文献2-5)。同时,禁食也抑制脂质的存储和合成(脂肪生成)途径,但其潜在机制尚不清楚。在这里,我们显示缺乏CREB活性的小鼠具有脂肪肝表型,并显示出核激素受体PPAR-γ(脂肪形成基因的关键调节剂)的表达升高。 CREB通过刺激分裂多毛增强子(HES-1)基因的表达来抑制禁食状态下的肝PPAR-γ表达,HES-1基因是一种转录抑制因子,在此处显示是体内禁食脂质代谢的介质。禁食期间CREB对PGC-1的协同诱导和CREB抑制PPAR-γ为胰岛素与反调节激素之间的拮抗作用提供了分子基础,并表明CREB拮抗剂作为治疗剂在增强肝脏对胰岛素敏感性方面的潜在作用。

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