Lan Fan, Weikel Karen A, Cacicedo Jose M, Ido Yasuo
The First People's Hospital of Chongqing Liang Jiang New Area, Chongqing 401122, China.
Division of Natural Sciences & Mathematics, Boston University College of General Studies, Boston, MA 02215, USA.
Nutrients. 2017 Jul 14;9(7):751. doi: 10.3390/nu9070751.
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.
尽管白藜芦醇具有良好的效果，但其在临床上的疗效仍存在争议。我们是首个报道SIRT1激活剂白藜芦醇可激活AMP激活的蛋白激酶（AMPK）的团队（《糖尿病》，2005年；54：A383），并且我们认为该级联反应的变异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，诸如白藜芦醇之类的SIRT1激活剂的作用可能不仅通过激活SIRT1，还通过SIRT1-肝脏激酶B1（LKB1）-AMPK的综合作用。在这种情况下，白藜芦醇通过以下方式激活SIRT1：（1）直接与SIRT1结合；（2）通过激活Nampt上调补救途径来增加NAD⁺水平，这是一种由AMPK介导的作用。第一种机制促进有限数量的SIRT1底物蛋白（例如PGC-1）的去乙酰化。第二种机制（可能比第一种更重要）除了激活SIRT1外还激活其他sirtuins，这会影响广泛的底物。尽管有这些发现，但尚未报道白藜芦醇激活AMPK的详细机制。在此，我们表明：（1）白藜芦醇诱导的AMPK激活需要功能性LKB1的存在；（2）白藜芦醇增加LKB1的活性，这涉及T336和S428处的易位和磷酸化；（3）LKB1的激活导致LKB1的蛋白酶体降解；（4）在高浓度（50-100μM）下，白藜芦醇还通过增加AMP水平来激活AMPK；（5）上述激活机制在不同细胞类型中有所不同，并且在某些细胞类型中，白藜芦醇无法激活AMPK。这些结果表明白藜芦醇诱导的AMPK激活并非普遍现象。此外，第二种机制中AMPK介导的NAD⁺增加需要几个ATP，而在许多病理情况下可能无法获得这些ATP。这些现象可能解释了为什么白藜芦醇在临床环境中并不总是始终有益的。
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