Xanthene Derivatives Increase Glucose Utilization through Activation of LKB1-Dependent AMP-Activated Protein Kinase
Xanthene Derivatives Increase Glucose Utilization through Activation of LKB1-Dependent AMP-Activated Protein Kinase
复制标题
呫吨衍生物通过激活 LKB1 依赖性 AMP 激活蛋白激酶来增加葡萄糖利用率
作者：
Yonghoon Kwon;Parkyong Song;J. Yoon;Jaewang Ghim;Dayea Kim;B. Kang;Taehoon G. Lee;Jin;Joong;I. Youn;Hyeongjoo Lee;S. Ryu
5′-腺苷酸活化蛋白激酶（AMPK）是一种高度保守的丝氨酸-苏氨酸激酶，通过激活分解代谢和抑制合成代谢途径来调节能量消耗，从而提高细胞能量水平。因此，AMPK激活剂被认为是治疗代谢疾病如糖尿病的药物靶标。为了鉴定新型AMPK激活剂，我们筛选了咕吨衍生物。我们确定AMPK激活剂9 H-咕吨-9-羧酸{2，2，2-三氯-1-[3-（3-硝基-苯基）-硫脲基]-乙基}-酰胺（Xn）和9 H-咕吨-9-羧酸{2，2，2-三氯-1-[3-（3-氰基-苯基）-硫脲基]-乙基}-酰胺（Xc）通过刺激葡萄糖转运蛋白4（GLUT 4）的易位来增加L 6肌管中的葡萄糖摄取。用化学AMPK抑制剂化合物C处理和用显性阴性AMPKa 2病毒感染抑制了由Xn或XC诱导的肌管中AMPK磷酸化和葡萄糖摄取。在AMPK的两种主要上游激酶中，我们发现Xn和Xc通过敲低STK 11（人类LKB 1的直系同源物）显示出LKB 1依赖性。对高脂饮食诱导的糖尿病小鼠单次静脉给予Xn和XC刺激骨骼肌AMPK磷酸化并改善葡萄糖耐量。综上所述，这些结果表明，Xn和XC调节葡萄糖稳态通过LKB 1依赖性AMPK激活和化合物是潜在的候选药物用于治疗2型糖尿病。
5′ AMP-activated protein kinase (AMPK) is a highly conserved serine-threonine kinase that regulates energy expenditure by activating catabolic metabolism and suppressing anabolic pathways to increase cellular energy levels. Therefore AMPK activators are considered to be drug targets for treatment of metabolic diseases such as diabetes mellitus. To identify novel AMPK activators, we screened xanthene derivatives. We determined that the AMPK activators 9H-xanthene-9-carboxylic acid {2,2,2-trichloro-1-[3-(3-nitro-phenyl)-thioureido]-ethyl}-amide (Xn) and 9H-xanthene-9-carboxylic acid {2,2,2-trichloro-1-[3-(3-cyano-phenyl)-thioureido]-ethyl}-amide (Xc) elevated glucose uptake in L6 myotubes by stimulating translocation of glucose transporter type 4 (GLUT4). Treatment with the chemical AMPK inhibitor compound C and infection with dominant-negative AMPKa2-virus inhibited AMPK phosphorylation and glucose uptake in myotubes induced by either Xn or Xc. Of the two major upstream kinases of AMPK, we found that Xn and Xc showed LKB1 dependency by knockdown of STK11, an ortholog of human LKB1. Single intravenous administration of Xn and Xc to high-fat diet-induced diabetic mice stimulated AMPK phosphorylation of skeletal muscle and improved glucose tolerance. Taken together, these results suggest that Xn and Xc regulate glucose homeostasis through LKB1-dependent AMPK activation and that the compounds are potential candidate drugs for the treatment of type 2 diabetes mellitus.
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影响因子：
7.7
作者：
Musi, N;Hirshman, MF;Goodyear, LJ
通讯作者：
Goodyear, LJ
DOI：
--
发表时间：
1999
期刊：
--
影响因子：
--
作者：
E. J. Kurth-Kraczek;M. Hirshman;L. Goodyear;William W. Wi
通讯作者：
E. J. Kurth-Kraczek;M. Hirshman;L. Goodyear;William W. Wi
DOI：
10.1152/ajpendo.00453.2005
发表时间：
2006-07-01
影响因子：
5.1
作者：
LeBrasseur, Nathan K.;Kelly, Meghan;Tomas, Eva
通讯作者：
Tomas, Eva
DOI：
10.1152/ajpendo.00211.2007
发表时间：
2008-01-01
影响因子：
5.1
作者：
Yin, Jun;Gao, Zhanguo;Ye, Jianping
通讯作者：
Ye, Jianping