Metformin suppresses hepatic gluconeogenesis through induction of SIRT1 and GCN5
Metformin suppresses hepatic gluconeogenesis through induction of SIRT1 and GCN5
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DOI：
10.1677/joe-09-0345
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发表时间：
2010-04-01
影响因子：
4
通讯作者：
Corder, Roger
中科院分区：
文献类型：
--
作者：
Caton, Paul W.;Nayuni, Nanda K.;Corder, Roger
肝再生异常升高是2型糖尿病（T2 DM）患者发生高血糖的关键。二甲双胍通过抑制血管生成纠正高血糖症，但其作用机制尚未完全阐明。SIRT 1和GCN 5（在MGI数据库中被列为KAT 2A）最近被鉴定为通过调节辅激活因子cAMP-反应元件结合蛋白-调节转录辅激活因子2的水平和活性来调节致肿瘤基因表达的调节因子（TORC 2或CRTC 2，如MGI数据库中所列）和过氧化物酶体增殖物激活受体-γ共激活因子-1 α（PGC 1 α或PPARGC 1A，如MGI数据库中所列）。我们报告说，在db/db小鼠中，与未治疗的db/db小鼠相比，二甲双胍（250 mg/kg/天; 7天）增加了肝脏GCN 5蛋白和mRNA的水平，并且相对于对照和未治疗的db/db小鼠，增加了SIRT 1蛋白和活性的水平。这些变化与TORC 2蛋白水平降低、PGC 1 α靶基因磷酸烯醇丙酮酸羧激酶的基因表达和激活降低以及血糖和胰岛素降低相关。抑制SIRT 1可部分阻断二甲双胍对新生血管的影响。SIRT 1通过AMP活化蛋白激酶介导的烟酰胺磷酸核糖基转移酶基因表达的增加而增加，烟酰胺磷酸核糖基转移酶是NAD（+）补救途径的限速酶。此外，与对照组相比，db/db小鼠中GCN 5的水平显著降低。这表明，GCN 5介导的对肝脏新生的抑制作用的丧失似乎构成了db/db小鼠中肝脏葡萄糖产生异常升高的主要机制。总之，GCN 5和SIRT 1的诱导可能代表二甲双胍的关键作用机制。此外，这些数据确定诱导肝GCN 5作为治疗T2 DM的潜在治疗策略。内分泌学杂志（2010）205，97-106
Abnormal elevation of hepatic gluconeogenesis is central to the onset of hyperglycaemia in patients with type 2 diabetes mellitus (T2DM). Metformin corrects hyperglycaemia through inhibition of gluconeogenesis, but its mechanism of action is yet to be fully described. SIRT1 and GCN5 (listed as KAT2A in the MGI Database) have recently been identified as regulators of gluconeogenic gene expression through modulation of levels and activity of the coactivators cAMP-response element binding protein-regulated transcription coactivator 2 (TORC2 or CRTC2 as listed in the MGI Database) and peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC1 alpha or PPARGC1A as listed in the MGI Database). We report that in db/db mice, metformin (250 mg/kg per day; 7 days) increases hepatic levels of GCN5 protein and mRNA compared with the untreated db/db mice, as well as increases levels of SIRT1 protein and activity relative to controls and untreated db/db mice. These changes were associated with reduced TORC2 protein level and decreased gene expression and activation of the PGC1 alpha gene target phosphoenolpyruvate carboxykinase, and lower plasma glucose and insulin. Inhibition of SIRT1 partially blocked the effects of metformin on gluconeogenesis. SIRT1 was increased through an AMP-activated protein kinase-mediated increase in gene expression of nicotinamide phosphoribosyltransferase, the rate-limiting enzyme of the salvage pathway for NAD(+). Moreover, levels of GCN5 were dramatically reduced in db/db mice compared with the controls. This indicates that loss of GCN5-mediated inhibition of gluconeogenesis appears to constitute a major mechanism for the onset of abnormally elevated hepatic glucose production in db/db mice. In conclusion, induction of GCN5 and SIRT1 potentially represents a critical mechanism of action of metformin. In addition, these data identify induction of hepatic GCN5 as a potential therapeutic strategy for treatment of T2DM. Journal of Endocrinology (2010) 205, 97-106