Metformin reduces hepatic expression of SIRT3, the mitochondrial deacetylase controlling energy metabolism.
Metformin reduces hepatic expression of SIRT3, the mitochondrial deacetylase controlling energy metabolism.
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DOI：
10.1371/journal.pone.0049863
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Hakkola J
中科院分区：
文献类型：
--
作者：
Buler M;Aatsinki SM;Izzi V;Hakkola J
二甲双胍抑制线粒体中ATP的产生，这可能与药物的抗高血糖作用有关。Sirtuin 3（SIRT 3）是一种线粒体蛋白脱乙酰酶，其调节电子传递链的功能并维持基础ATP产量。我们假设二甲双胍治疗可以通过下调SIRT 3表达来减少线粒体ATP的产生。胰高血糖素和cAMP诱导小鼠原代肝细胞中SIRT 3 mRNA的表达。二甲双胍阻止胰高血糖素对SIRT 3的诱导。此外，二甲双胍在体内下调原代肝细胞和肝脏中SIRT 3的组成型表达。雌激素相关受体α（ERRα）介导过氧化物酶体增殖物激活受体γ辅激活因子1 α（PGC-1α）对Sirt 3基因的调控。ERRα mRNA表达受胰高血糖素、cAMP和二甲双胍的调节方式与SIRT 3 mRNA相似。然而，ERRα下调所需的二甲双胍浓度高于SIRT 3。ERRα siRNA减弱了PGC-1α介导的SIRT 3的诱导作用，但不影响SIRT 3的组成型表达。AMP活化蛋白激酶（AMPK）组成型活性形式的过表达诱导SIRT 3 mRNA，表明二甲双胍下调SIRT 3不是由AMPK介导的。二甲双胍降低肝细胞ATP水平。这种作用被SIRT 3过表达部分抵消。此外，二甲双胍降低了线粒体SIRT 3蛋白水平，这与几种线粒体蛋白的乙酰化增强有关。然而，二甲双胍增加了肝细胞中的线粒体质量。总之，我们的研究结果表明，二甲双胍减弱SIRT 3的线粒体表达，并表明该机制涉及二甲双胍在肝脏中调节能量代谢，并可能有助于二甲双胍的治疗作用。
Metformin inhibits ATP production in mitochondria and this may be involved in the anti-hyperglycemic effects of the drug. Sirtuin 3 (SIRT3) is a mitochondrial protein deacetylase that regulates the function of the electron transport chain and maintains basal ATP yield. We hypothesized that metformin treatment could diminish mitochondrial ATP production through downregulation of SIRT3 expression. Glucagon and cAMP induced SIRT3 mRNA in mouse primary hepatocytes. Metformin prevented SIRT3 induction by glucagon. Moreover, metformin downregulated constitutive expression of SIRT3 in primary hepatocytes and in the liver in vivo. Estrogen related receptor alpha (ERRα) mediates regulation of Sirt3 gene by peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). ERRα mRNA expression was regulated in a similar manner as SIRT3 mRNA by glucagon, cAMP and metformin. However, a higher metformin concentration was required for downregulation of ERRα than SIRT3. ERRα siRNA attenuated PGC-1α mediated induction of SIRT3, but did not affect constitutive expression. Overexpression of the constitutively active form of AMP-activated protein kinase (AMPK) induced SIRT3 mRNA, indicating that the SIRT3 downregulation by metformin is not mediated by AMPK. Metformin reduced the hepatocyte ATP level. This effect was partially counteracted by SIRT3 overexpression. Furthermore, metformin decreased mitochondrial SIRT3 protein levels and this was associated with enhanced acetylation of several mitochondrial proteins. However, metformin increased mitochondrial mass in hepatocytes. Altogether, our results indicate that metformin attenuates mitochondrial expression of SIRT3 and suggest that this mechanism is involved in regulation of energy metabolism by metformin in the liver and may contribute to the therapeutic action of metformin.
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影响因子：
4
作者：
Caton, Paul W.;Nayuni, Nanda K.;Corder, Roger
通讯作者：
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影响因子：
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作者：
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Hakkola, Jukka
影响因子：
4.1
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通讯作者：
Hue, Louis
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作者：
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通讯作者：
Leverve, X