Novel small-molecule AMPK activator orally exerts beneficial effects on diabetic db/db mice
Novel small-molecule AMPK activator orally exerts beneficial effects on diabetic db/db mice
复制标题
口服新型小分子 AMPK 激活剂对糖尿病 db/db 小鼠产生有益作用
DOI：
10.1016/j.taap.2013.09.006
复制
发表时间：
2013-12-01
影响因子：
3.8
通讯作者：
Li, Jia
中科院分区：
文献类型：
--
作者：
Li, Yuan-Yuan;Yu, Li-Fang;Li, Jia
AMP激活的蛋白激酶(AMPK)是全身能量代谢的重要守护者，已成为代谢综合征的治疗靶点。以前，使用均相闪烁邻近分析，我们从最初的变构激活剂PT1的优化中鉴定了小分子AMPK激活剂C24。本文探讨了C24激活AMPK的机制及其对db/db小鼠糖脂代谢的潜在有益作用。C24通过拮抗自身抑制作用刺激AMPKα亚基截断失活并激活AMPK异源三聚体。在原代肝细胞中，C24呈剂量依赖性地增加AMPK下游靶标乙酰辅酶A羧基酶的磷酸化，但不改变细胞内AMP/ATP的比值，表明其在细胞内的变构激活。C24通过激活AMPK，下调原代肝细胞磷酸烯醇式丙酮酸羧激酶(PEPCK)和葡萄糖-6-磷酸酶(G6Pase)的mRNA水平，从而减少葡萄糖产量。C24还能降低HepG2细胞的甘油三酯和胆固醇含量。由于其生物利用度的提高，长期口服多剂量04可显著降低糖尿病db/db小鼠的血糖和血脂水平，并改善其糖耐量。肝脏PEPCK和G6Pase转录水平降低。这些结果表明，这种口服有效的AMPK激动剂是治疗代谢综合征的一种新方法。(C)2013 Elsevier Inc.保留所有权利。
AMP-activated protein kinase (AMPK), which is a pivotal guardian of whole-body energy metabolism, has become an attractive therapeutic target for metabolic syndrome. Previously, using a homogeneous scintillation proximity assay, we identified the small-molecule AMPK activator C24 from an optimization based on the original allosteric activator PT1. In this paper, the AMPK activation mechanism of C24 and its potential beneficial effects on glucose and lipid metabolism on db/db mice were investigated. C24 allosterically stimulated inactive AMPK alpha subunit truncations and activated AMPK heterotrimers by antagonizing autoinhibition. In primary hepatocytes, C24 increased the phosphorylation of AMPK downstream target acetyl-CoA carboxylase dose-dependently without changing intracellular AMP/ATP ratio, indicating its allosteric activation in cells. Through activating AMPK, C24 decreased glucose output by down-regulating mRNA levels of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) in primary hepatocytes. C24 also decreased the triglyceride and cholesterol contents in HepG2 cells. Due to its improved bioavailability, chronic oral treatment with multiple doses of 04 significantly reduced blood glucose and lipid levels in plasma, and improved the glucose tolerance of diabetic db/db mice. The hepatic transcriptional levels of PEPCK and G6Pase were reduced. These results demonstrate that this orally effective activator of AMPK represents a novel approach to the treatment of metabolic syndrome. (C) 2013 Elsevier Inc. All rights reserved.