Inhibition of Endothelial p53 Improves Metabolic Abnormalities Related to Dietary Obesity
Inhibition of Endothelial p53 Improves Metabolic Abnormalities Related to Dietary Obesity
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DOI：
10.1016/j.celrep.2014.04.046
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发表时间：
2014-06-12
期刊：
影响因子：
8.8
通讯作者：
Minamino, Tohru
中科院分区：
文献类型：
--
作者：
Yokoyama, Masataka;Okada, Sho;Minamino, Tohru
越来越多的证据表明 p53 激活在各种与年龄相关的疾病中发挥着作用。在这里，我们确定了内皮 p53 激活在葡萄糖稳态调节中的关键作用。当给小鼠喂食高热量饮食时，p53 的内皮表达显着上调。内皮 p53 激活的破坏改善了内皮一氧化氮合酶的饮食失活，从而上调了骨骼肌中过氧化物酶体增殖物激活受体 - γ 辅激活剂 - 1 α 的表达，从而增加了线粒体的生物合成和耗氧量。与对照同窝小鼠相比，患有内皮细胞特异性 p53 缺陷的小鼠在喂食高热量饮食后，胰岛素敏感性得到改善，脂肪积累也减少。相反，内皮 p53 的上调会导致代谢异常。这些结果表明，抑制内皮 p53 可能是阻止与肥胖相关的心血管和代谢异常恶性循环的新治疗靶点。
Accumulating evidence has suggested a role for p53 activation in various age-associated conditions. Here, we identified a crucial role of endothelial p53 activation in the regulation of glucose homeostasis. Endothelial expression of p53 was markedly upregulated when mice were fed a high-calorie diet. Disruption of endothelial p53 activation improved dietary inactivation of endothelial nitric oxide synthase that upregulated the expression of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha in skeletal muscle, thereby increasing mitochondrial biogenesis and oxygen consumption. Mice with endothelial cell-specific p53 deficiency fed a high-calorie diet showed improvement of insulin sensitivity and less fat accumulation, compared with control littermates. Conversely, upregulation of endothelial p53 caused metabolic abnormalities. These results indicate that inhibition of endothelial p53 could be a novel therapeutic target to block the vicious cycle of cardiovascular and metabolic abnormalities associated with obesity.