Resveratrol-Induced AMP-Activated Protein Kinase Activation Is Cell-Type Dependent: Lessons from Basic Research for Clinical Application.
Resveratrol-Induced AMP-Activated Protein Kinase Activation Is Cell-Type Dependent: Lessons from Basic Research for Clinical Application.
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作者：
Lan F;Weikel KA;Cacicedo JM;Ido Y
尽管白藜芦醇具有良好的作用，但其在临床上的疗效仍存在争议。我们是第一个报告SIRT 1激活剂白藜芦醇激活AMP激活蛋白激酶（AMPK）的小组（Diabetes 2005; 54：A383），我们认为这种级联的可变性可能是白藜芦醇效果不一致的原因。我们目前的研究表明，SIRT 1激活剂如白藜芦醇的作用可能不仅仅是通过激活SIRT 1，还通过SIRT 1-肝激酶B1（LKB 1）-AMPK的综合作用。在这种情况下，白藜芦醇激活SIRT 1（1）通过直接结合SIRT 1;（2）通过增加NAD+水平，通过Nampt激活，一种由AMPK介导的效应，上调补救途径。第一种机制促进有限数量的SIRT 1底物蛋白（例如，PGC-1）。第二种机制（可能比第一种机制更重要）除了SIRT 1之外还激活其他sirtuins，这会影响广泛的底物。尽管有这些发现，白藜芦醇如何激活AMPK的详细机制尚未报道。在这里，我们发现：（1）白藜芦醇诱导的AMPK激活需要功能性LKB 1的存在;（2）白藜芦醇增加LKB 1的活性，这涉及T336和S428的易位和磷酸化;（3）LKB 1的激活导致LKB 1的蛋白酶体降解;（4）在高浓度下，（50-100 μM），白藜芦醇也通过增加AMP水平激活AMPK;和（5）上述激活机制在细胞类型中不同，在某些细胞类型中，白藜芦醇不能激活AMPK。这些结果表明，白藜芦醇诱导的AMPK激活不是一个普遍存在的现象。此外，在第二种机制中，AMPK介导的NAD+增加需要几种ATP，这在许多病理条件下可能无法获得。这些现象可以解释为什么白藜芦醇在临床环境中并不总是有益的。
Despite the promising effects of resveratrol, its efficacy in the clinic remains controversial. We were the first group to report that the SIRT1 activator resveratrol activates AMP-activated protein kinase (AMPK) (Diabetes 2005; 54: A383), and we think that the variability of this cascade may be responsible for the inconsistency of resveratrol’s effects. Our current studies suggest that the effect of SIRT1 activators such as resveratrol may not be solely through activation of SIRT1, but also through an integrated effect of SIRT1-liver kinase B1 (LKB1)-AMPK. In this context, resveratrol activates SIRT1 (1) by directly binding to SIRT1; and (2) by increasing NAD+ levels by upregulating the salvage pathway through Nampt activation, an effect mediated by AMPK. The first mechanism promotes deacetylation of a limited number of SIRT1 substrate proteins (e.g., PGC-1). The second mechanism (which may be more important than the first) activates other sirtuins in addition to SIRT1, which affects a broad spectrum of substrates. Despite these findings, detailed mechanisms of how resveratrol activates AMPK have not been reported. Here, we show that (1) resveratrol-induced activation of AMPK requires the presence of functional LKB1; (2) Resveratrol increases LKB1 activity, which involves translocation and phosphorylation at T336 and S428; (3) Activation of LKB1 causes proteasomal degradation of LKB1; (4) At high concentrations (50–100 µM), resveratrol also activates AMPK through increasing AMP levels; and (5) The above-mentioned activation mechanisms vary among cell types, and in some cell types, resveratrol fails to activate AMPK. These results suggest that resveratrol-induced activation of AMPK is not a ubiquitous phenomenon. In addition, AMPK-mediated increases in NAD+ in the second mechanism require several ATPs, which may not be available in many pathological conditions. These phenomena may explain why resveratrol is not always consistently beneficial in a clinical setting.
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DOI：
10.18632/aging.100542
发表时间：
2013-03
期刊：
Aging
影响因子：
--
作者：
Lakshminarasimhan M;Rauh D;Schutkowski M;Steegborn C
通讯作者：
Steegborn C
DOI：
10.1126/science.1231097
发表时间：
2013-03-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hubbard BP;Gomes AP;Dai H;Li J;Case AW;Considine T;Riera TV;Lee JE;E SY;Lamming DW;Pentelute BL;Schuman ER;Stevens LA;Ling AJ;Armour SM;Michan S;Zhao H;Jiang Y;Sweitzer SM;Blum CA;Disch JS;Ng PY;Howitz KT;Rolo AP;Hamuro Y;Moss J;Perni RB;Ellis JL;Vlasuk GP;Sinclair DA
通讯作者：
Sinclair DA
影响因子：
--
作者：
Hawley SA;Boudeau J;Reid JL;Mustard KJ;Udd L;Mäkelä TP;Alessi DR;Hardie DG
通讯作者：
Hardie DG
尼古丁酰胺腺苷二核苷酸氧化还原，胰岛素C肽，SIRTUIN 1肝激酶B1-腺苷单磷酸激活的蛋白激酶阳性反馈和叉子盒O3。
影响因子：
3.2
作者：
Ido Y
通讯作者：
Ido Y
影响因子：
3
作者：
Beher, Dirk;Wu, John;Wang, Minghan
通讯作者：
Wang, Minghan