Abstract：
Nuclear receptor corepressors (NCoRs) function in multiprotein complexes containing histone deacetylase 3 (HDAC3) to alter transcriptional output primarily through repressive chromatin remodelling at target loci1-5. In the liver, loss of HDAC3 causes a marked hepatosteatosis largely because of de-repression of genes involved in lipid metabolism6,7; however, the individual roles and contribution of other complex members to hepatic and systemic metabolic regulation are unclear. Here we show that adult loss of both NCoR1 and NCoR2 (double knockout (KO)) in hepatocytes phenocopied the hepatomegalic fatty liver phenotype of HDAC3 KO. In addition, double KO livers exhibited a dramatic reduction in glycogen storage and gluconeogenic gene expression that was not observed with hepatic KO of individual NCoRs or HDAC3, resulting in profound fasting hypoglycaemia. This surprising HDAC3-independent activation function of NCoR1 and NCoR2 is due to an unexpected loss of chromatin accessibility on deletion of NCoRs that prevented glucocorticoid receptor binding and stimulatory effect on gluconeogenic genes. These studies reveal an unanticipated, non-canonical activation function of NCoRs that is required for metabolic health.
摘要：
在含有组蛋白脱乙酰酶3（HDAC3）的多蛋白复合物中，核受体协同抑制因子（NCoRs）的功能主要是通过在靶标loc1-5处进行抑制性染色质重塑来改变转录输出。在肝脏中，HDAC3的丢失导致明显的肝骨化病，主要是由于参与脂质代谢的基因的去抑制6,7;然而，其他复杂成员对肝脏和全身代谢调节的个体作用和贡献尚不清楚.在这里，我们显示，NCoR1和NCoR2（双敲除（KO））在肝细胞中的成人损失表型表现为HDAC3KO的肝大脂肪肝表型。此外,双KO肝脏表现出糖原储存和糖异生基因表达的显著减少,这在单个NCoRs或HDAC3的肝脏KO中未观察到,导致严重的空腹低血糖.NCoR1和NCoR2的这种令人惊讶的HDAC3非依赖性激活功能是由于NCoR缺失时染色质可及性的意外损失，从而阻止了糖皮质激素受体结合和对糖异生基因的刺激作用。这些研究揭示了一个意想不到的，代谢健康所需的NCoRs的非规范激活功能。
