The deacetylase Sirt6 activates the acetyltransferase GCN5 and suppresses hepatic gluconeogenesis.-猫眼课题宝

DOI：

10.1016/j.molcel.2012.09.030

发表时间：

2012-12-28

期刊：

MOLECULAR CELL

影响因子：

通讯作者：

中科院分区：

生物学1区

文献类型：

作者：

Dominy, John E., Jr.;Lee, Yoonjin;Jedrychowski, Mark P.;Chim, Helen;Jurczak, Michael J.;Camporez, Joao Paulo;Ruan, Hai-Bin;Feldman, Jessica;Pierce, Kerry;Mostoslavsky, Raul;Denu, John M.;Clish, Clary B.;Yang, Xiaoyong;Shulman, Gerald I.;Gygi, Steven P.;Puigserver, Pere

来源链接：

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3534905/?report=classic

肝脏葡萄糖产生(HGP)在禁食期间维持血糖水平，但也会加重糖尿病高血糖。HGP是由一个信号/转录网络动态控制的，该网络调节糖异生酶的表达/活性。糖异生基因转录的关键调节因子是pGC-1α。PGC-1αS对糖异生基因表达的激活依赖于其乙酰化状态，其乙酰化状态受乙酰基转移酶GCN5和去乙酰基酶Sirt1控制。然而，其他染色质修饰剂，特别是其他sirtuins是否可以调节pGC-1α乙酰化目前尚不清楚。在此，我们报道了SIRT6强烈控制pGC-1α乙酰化。令人惊讶的是，SIRT6诱导PGC-1α乙酰化并抑制Hgp。SIRT6缺失降低了PGC-1的α乙酰化，促进了Hgp。这些乙酰化作用是依赖于GCN5的：SIRT6与GCN5相互作用并修饰GCN5，增强GCN5的S活性。Leprdb/Leprdb小鼠是一种肥胖/糖尿病动物模型，表现出SIRT6水平降低；异位重新表达抑制糖异生基因并使血糖正常化。因此，肝脏SIRT6的激活可能在治疗胰岛素抵抗糖尿病方面有用。

Hepatic glucose production (HGP) maintains blood glucose levels during fasting but can also exacerbate diabetic hyperglycemia. HGP is dynamically controlled by a signaling/transcriptional network that regulates the expression/activity of gluconeogenic enzymes. A key mediator of gluconeogenic gene transcription is PGC-1α. PGC-1α’s activation of gluconeogenic gene expression is dependent upon its acetylation state, which is controlled by the acetyltransferase GCN5 and the deacetylase Sirt1. Nevertheless, whether other chromatin modifiers—particularly other sirtuins—can modulate PGC-1α acetylation is currently unknown. Herein we report that Sirt6 strongly controls PGC-1α acetylation. Surprisingly, Sirt6 induces PGC-1α acetylation and suppresses HGP. Sirt6 depletion decreases PGC-1α acetylation and promotes HGP. These acetylation effects are GCN5 dependent: Sirt6 interacts with and modifies GCN5, enhancing GCN5’s activity. Leprdb/Leprdb mice, an obese/diabetic animal model, exhibit reduced Sirt6 levels; ectopic re-expression suppresses gluconeogenic genes and normalizes glycemia. Activation of hepatic Sirt6 may therefore be therapeutically useful for treating insulin-resistant diabetes.