Aberrant activation of AMP-activated protein kinase remodels metabolic network in favor of cardiac glycogen storage
Aberrant activation of AMP-activated protein kinase remodels metabolic network in favor of cardiac glycogen storage
复制标题
DOI：
10.1172/jci30658
复制
发表时间：
2007-05-01
影响因子：
15.9
通讯作者：
Tian, Rong
中科院分区：
文献类型：
--
作者：
Luptak, Ivan;Shen, Mei;Tian, Rong
AMP 激活蛋白激酶 (AMPK) 通过刺激底物代谢产生 ATP，对受损的细胞能量状态做出反应。人类 AMPK 的 γ2 调节亚基突变使激酶对能量状态不敏感，并通过未知机制引起糖原贮积性心肌病。使用在心脏中表达一种突变型γ2亚基（N488I）的转基因小鼠，我们发现在没有能量缺乏的情况下，AMPK的异常高活性导致底物代谢途径的广泛重塑，以通过独特但协同的机制来适应γ2突变型小鼠心脏中葡萄糖摄取和脂肪酸氧化的增加，从而导致选择性燃料储存为糖原。 γ2突变小鼠心脏中增加的葡萄糖进入通过重塑的代谢网络引导至糖原合成，并且在显着更高的糖原水平下，通过糖原库循环进入糖酵解。因此，在没有能量缺乏的情况下 AMPK 慢性激活的代谢后果与之前报道的应激条件下的代谢后果不同。这些发现对于将 AMPK 作为代谢疾病治疗的靶点特别重要。
AMP-activated protein kinase (AMPK) responds to impaired cellular energy status by stimulating substrate metabolism for ATP generation. Mutation of the gamma 2 regulatory subunit of AMPK in humans renders the kinase insensitive to energy status and causes glycogen storage cardiomyopathy via unknown mechanisms. Using transgenic mice expressing one of the mutant gamma 2 subunits (N488I) in the heart, we found that aberrant high activity of AMPK in the absence of energy deficit caused extensive remodeling of the substrate metabolism pathways to accommodate increases in both glucose uptake and fatty acid oxidation in the hearts of gamma 2 mutant mice via distinct, yet synergistic mechanisms resulting in selective fuel storage as glycogen. Increased glucose entry in the gamma 2 mutant mouse hearts was directed through the remodeled metabolic network toward glycogen synthesis and, at a substantially higher glycogen level, recycled through the glycogen pool to enter glycolysis. Thus, the metabolic consequences of chronic activation of AMPK in the absence of energy deficiency is distinct from those previously reported during stress conditions. These findings are of particular importance in considering AMPK as a target for the treatment of metabolic diseases.