Glucagon-induced extracellular cAMP regulates hepatic lipid metabolism
Glucagon-induced extracellular cAMP regulates hepatic lipid metabolism
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胰高血糖素诱导的细胞外cAMP调节肝脂质代谢
DOI：
10.1530/joe-16-0649
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发表时间：
2017-08-01
影响因子：
4
通讯作者：
Luan, Bing
中科院分区：
文献类型：
--
作者：
Lv, Sihan;Qiu, Xinchen;Luan, Bing
在禁食期间，激素信号有助于维持肝脏中葡萄糖和脂肪的动态平衡。胰升糖素是一种由禁食诱导的胰源性激素，通过诱导细胞内cAMP的产生来促进糖异生。胰高血糖素也能刺激肝脏脂肪酸氧化，但其潜在机制尚不清楚。本文报道了在cAMP反应元件结合蛋白(CREB)诱导葡萄糖异生基因葡萄糖6磷酸酶(G6Pase)和磷酸烯醇式丙酮酸羧激酶(PEPCK)表达后，胰升糖素通过细胞外cAMP触发脂肪酸氧化基因酰辅酶A氧化酶(AOX)和肉碱棕榈酰转移酶1a(CPT1a)表达的第二个延迟期。细胞外cAMP的增加通过AMPK的直接磷酸化促进PPARα的活性，而抑制cAMP外流则大大减弱AOX和CPT1a的表达。重要的是，cAMP注射改善了禁食小鼠和肥胖小鼠的脂质稳态，而抑制cAMP外流则加重了禁食小鼠的肝脏脂肪变性。综上所述，我们的结果表明，高血糖素刺激的细胞外cAMP通过AMPK介导的PPARα激活在调节肝脏脂质代谢中起着至关重要的作用。因此，改善cAMP外流的策略可能成为预防肥胖相关性肝脏脂肪变性的潜在新工具。
Hormonal signals help to maintain glucose and lipid homeostasis in the liver during the periods of fasting. Glucagon, a pancreas-derived hormone induced by fasting, promotes gluconeogenesis through induction of intracellular cAMP production. Glucagon also stimulates hepatic fatty acid oxidation but the underlying mechanism is poorly characterized. Here we report that following the acute induction of gluconeogenic genes Glucose 6 phosphatase (G6Pase) and Phosphoenolpyruvate carboxykinase (Pepck) expression through cAMP-response element-binding protein (CREB), glucagon triggers a second delayed phase of fatty acid oxidation genes Acyl-coenzyme A oxidase (Aox) and Carnitine palmitoyltransferase 1a (Cpt1a) expression via extracellular cAMP. Increase in extracellular cAMP promotes PPAR alpha activity through direct phosphorylation by AMP-activated protein kinase (AMPK), while inhibition of cAMP efflux greatly attenuates Aox and Cpt1a expression. Importantly, cAMP injection improves lipid homeostasis in fasted mice and obese mice, while inhibition of cAMP efflux deteriorates hepatic steatosis in fasted mice. Collectively, our results demonstrate the vital role of glucagon-stimulated extracellular cAMP in the regulation of hepatic lipid metabolism through AMPK-mediated PPAR alpha activation. Therefore, strategies to improve cAMP efflux could serve as potential new tools to prevent obesity-associated hepatic steatosis.