High-throughput assay for modulators of mitochondrial membrane potential identifies a novel compound with beneficial effects on db/db mice.
High-throughput assay for modulators of mitochondrial membrane potential identifies a novel compound with beneficial effects on db/db mice.
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作者：
Qiu BY;Turner N;Li YY;Gu M;Huang MW;Wu F;Pang T;Nan FJ;Ye JM;Li JY;Li J
最近，一些药物已被证明可以通过温和调节线粒体功能对代谢综合征发挥有益作用。因此，我们探索了一种针对线粒体功能来改善葡萄糖和脂质代谢的策略。线粒体膜电位（Δψm）是线粒体功能的标志；因此，我们在 L6 肌管中建立了 Δψm 的高通量筛选试验。在体外和体内研究了选定的先导化合物对代谢综合征的影响。通过这种高通量筛选，鉴定出了一种新型小分子化合物 C1。 C1 使 L6 肌管中的 Δψm 去极化，但没有细胞毒性，并导致细胞 AMP 与 ATP 比率增加、AMP 激活蛋白激酶 (AMPK) 激活和葡萄糖摄取增强。它还刺激 HepG2 细胞中的 AMPK 通路，导致脂质含量降低。有趣的是，C1 抑制 L6 肌管的呼吸，但不影响分离的肌肉线粒体的呼吸，表明它可能通过影响电子供体的供应来间接去极化 Δψm。 C57BL/6J 小鼠急性给予 C1 显着增加肝脏中的脂肪氧化以及 AMPK 和乙酰辅酶 A 羧化酶的磷酸化。在糖尿病 db/db 小鼠中，长期服用 C1 可显着降低高血糖、血浆脂肪酸、葡萄糖不耐受以及肝脏中磷酸烯醇丙酮酸羧激酶和葡萄糖-6-磷酸酶的 mRNA 水平。我们的结果证明了一种新型小分子，可以温和地去极化 Δψm，并且能够改善葡萄糖和脂质代谢，从而对代谢综合征发挥有益作用。这些发现表明调节线粒体功能的化合物可能具有治疗 2 型糖尿病的潜力。
Recently, several drugs have been shown to exert beneficial effects for metabolic syndrome through mild regulation of mitochondrial function. Hence, we explored a strategy of targeting mitochondrial function to improve glucose and lipid metabolism. Mitochondrial membrane potential (Δψm) is a marker of mitochondrial function; therefore, we set up a high-throughput screening assay of Δψm in L6 myotubes. The effects of a selected lead compound were investigated in vitro and in vivo in relation to metabolic syndrome. A novel small-molecule compound, C1, was identified through this high-throughput screening. C1 depolarized Δψm in L6 myotubes without cytotoxicity and led to increased cellular AMP-to-ATP ratio, activation of AMP-activated protein kinase (AMPK), and enhanced glucose uptake. It also stimulated the AMPK pathway in HepG2 cells, leading to decreased lipid content. Intriguingly, C1 inhibited respiration in L6 myotubes but did not affect respiration in isolated muscle mitochondria, suggesting that it may depolarize Δψm indirectly by affecting the supply of electron donors. Acute administration of C1 in C57BL/6J mice markedly increased fat oxidation and the phosphorylation of AMPK and acetyl-CoA carboxylase in the liver. In diabetic db/db mice, chronic administration of C1 significantly reduced hyperglycemia, plasma fatty acids, glucose intolerance, and the mRNA levels of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase in the liver. Our results demonstrate a novel small molecule that mildly depolarizes Δψm and is able to improve glucose and lipid metabolism to exert beneficial effects for metabolic syndrome. These findings suggest that compounds regulating mitochondrial function may have therapeutic potential for type 2 diabetes.
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影响因子：
7.7
作者：
Guigas, B;Bertrand, L;Hue, L
通讯作者：
Hue, L
影响因子：
4.8
作者：
Koo, SH;Towle, HC
通讯作者：
Towle, HC
影响因子：
7.4
作者：
Kosaka, T;Okuyama, R;Ichikawa, K
通讯作者：
Ichikawa, K
影响因子：
7.7
作者：
Iglesias, MA;Ye, JM;Kraegen, EW
通讯作者：
Kraegen, EW
DOI：
10.1046/j.1467-789x.2001.00043.x
发表时间：
2001-11-01
期刊：
Obesity reviews : an official journal of the International Association for the Study of Obesity
影响因子：
--
作者：
Harper, J A;Dickinson, K;Brand, M D
通讯作者：
Brand, M D