Nischarin 抑制通过激活 AMP 激活的蛋白激酶来改变能量代谢。,Journal of Biological Chemistry

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Nischarin 抑制通过激活 AMP 激活的蛋白激酶来改变能量代谢。
Journal of Biological Chemistry ( IF 4.0 ) Pub Date : 2017-08-24 , DOI: 10.1074/jbc.m117.784256
Shengli Dong ₁ , Somesh Baranwal _{1,

2} , Anapatricia Garcia ₃ , Silvia J Serrano-Gomez _{1,

4} , Steven Eastlack ₁ , Tomoo Iwakuma ₅ , Donald Mercante ₆ , Franck Mauvais-Jarvis ₇ , Suresh K Alahari ₈

Affiliation

Nischarin (Nisch) 是一种关键蛋白质，可作为分子支架发挥作用，从而承载与多种蛋白质伙伴的相互作用。为了探索 Nisch 的生理重要性，我们在这里生成了 Nisch 功能丧失突变小鼠并分析了它们的代谢表型。Nisch 突变胚胎表现出发育迟缓，特点是体积小和体重增加减弱。我们通过显示 Nisch 结合并抑制 AMP 活化蛋白激酶 (AMPK) 的活性来揭示这种表型的原因，AMPK 通过抑制合成代谢和激活分解代谢过程来调节能量稳态。Nisch 突变增强了 AMPK 激活并抑制了小鼠胚胎成纤维细胞以及突变小鼠肌肉和肝脏组织中雷帕霉素信号传导的机制目标。尽管总体食物摄入量减少，但 Nisch 突变小鼠的葡萄糖氧化率也随着能量消耗的增加而增加。此外，Nisch 突变小鼠的肝糖异生标志物表达降低，与葡萄糖耐量增加有关。结果，这些小鼠表现出生长和体重下降。总之，我们的结果表明 Nisch 是一种重要的 AMPK 抑制剂和能量稳态的关键调节剂，包括脂质和葡萄糖代谢。

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Nischarin inhibition alters energy metabolism by activating AMP-activated protein kinase.

Nischarin (Nisch) is a key protein functioning as a molecular scaffold and thereby hosting interactions with several protein partners. To explore the physiological importance of Nisch, here we generated Nisch loss-of-function mutant mice and analyzed their metabolic phenotype. Nisch-mutant embryos exhibited delayed development, characterized by small size and attenuated weight gain. We uncovered the reason for this phenotype by showing that Nisch binds to and inhibits the activity of AMP-activated protein kinase (AMPK), which regulates energy homeostasis by suppressing anabolic and activating catabolic processes. The Nisch mutations enhanced AMPK activation and inhibited mechanistic target of rapamycin signaling in mouse embryonic fibroblasts as well as in muscle and liver tissues of mutant mice. Nisch-mutant mice also exhibited increased rates of glucose oxidation with increased energy expenditure, despite reduced overall food intake. Moreover, the Nisch-mutant mice had reduced expression of liver markers of gluconeogenesis associated with increased glucose tolerance. As a result, these mice displayed decreased growth and body weight. Taken together, our results indicate that Nisch is an important AMPK inhibitor and a critical regulator of energy homeostasis, including lipid and glucose metabolism.

更新日期：2019-11-01

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