The glucocorticoid receptor controls hepatic dyslipidemia through Hes1
The glucocorticoid receptor controls hepatic dyslipidemia through Hes1
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DOI：
10.1016/j.cmet.2008.08.001
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发表时间：
2008-09-03
期刊：
影响因子：
29
通讯作者：
Herzig, Stephan
中科院分区：
文献类型：
--
作者：
Lemke, Ulrike;Krones-Herzig, Anja;Herzig, Stephan
脂质在肝脏中的异常积累（“脂肪肝”或肝性脂肪变性）代表代谢综合征的标志，并且与肥胖、II型糖尿病、饥饿或糖皮质激素（GC）治疗密切相关。虽然脂肪肝与许多肝功能异常有关，但脂肪肝发展的分子机制在很大程度上仍然是个谜。在这里，我们表明，肝脏特异性破坏糖皮质激素受体（GR）的作用，改善脂肪肝小鼠模型的脂肪变性表型，并导致转录抑制因子分裂1（Hes1）基因表达的毛状增强子的诱导。GR直接干扰Hes1启动子活性，触发组蛋白脱乙酰酶（HDAC）活性的Hes1基因的招聘。脂肪变性动物肝脏Hes 1水平的遗传恢复使肝脏甘油三酯（TG）水平正常化。由于糖皮质激素的作用在饥饿、强直性肌营养不良和库欣综合征期间增加，通过GR抑制Hes 1可能解释这些受试者的脂肪肝表型。
Aberrant accumulation of lipids in the liver ("fatty liver" or hepatic steatosis) represents a hallmark of the metabolic syndrome and is tightly associated with obesity, type II diabetes, starvation, or glucocorticoid (GC) therapy. While fatty liver has been connected with numerous abnormalities of liverfunction, the molecular mechanisms of fatty liver development remain largely enigmatic. Here we show that liver-specific disruption of glucocorticoid receptor (GR) action improves the steatotic phenotype in fatty liver mouse models and leads to the induction of transcriptional repressor hairy enhancer of split 1 (Hes1) gene expression. The GR directly interferes with Hes1 promoter activity, triggering the recruitment of histone deacetylase (HDAC) activities to the Hes1 gene. Genetic restoration of hepatic Hes1 levels in steatotic animals normalizes hepatic triglyceride (TG) levels. As glucocorticoid action is increased during starvation, myotonic dystrophy, and Cushing's syndrome, the inhibition of Hes1 through the GR might explain the fatty liver phenotype in these subjects.