Lv Sihan, Qiu Xinchen, Li Jian, Liang Jinye, Li Weida, Zhang Chao, Zhang Zhen-Ning, Luan Bing
Department of EndocrinologyShanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
Translational Medical Center for Stem Cell Therapy & Institute for Regenerative MedicineShanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China.
J Endocrinol. 2017 Aug;234(2):73-87. doi: 10.1530/JOE-16-0649. Epub 2017 May 17.
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 () and () expression through cAMP-response element-binding protein (CREB), glucagon triggers a second delayed phase of fatty acid oxidation genes () and () expression via extracellular cAMP. Increase in extracellular cAMP promotes PPARα activity through direct phosphorylation by AMP-activated protein kinase (AMPK), while inhibition of cAMP efflux greatly attenuates and 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 PPARα activation. Therefore, strategies to improve cAMP efflux could serve as potential new tools to prevent obesity-associated hepatic steatosis.
在禁食期间，激素信号有助于维持肝脏中的葡萄糖和脂质稳态。胰高血糖素是一种由禁食诱导产生的源自胰腺的激素，它通过诱导细胞内cAMP生成来促进糖异生。胰高血糖素还刺激肝脏脂肪酸氧化，但其潜在机制尚未完全明确。在此，我们报告称，通过cAMP反应元件结合蛋白（CREB）急性诱导糖异生基因（）和（）表达后，胰高血糖素通过细胞外cAMP触发脂肪酸氧化基因（）和（）表达的第二个延迟阶段。细胞外cAMP的增加通过AMP激活的蛋白激酶（AMPK）的直接磷酸化促进PPARα活性，而抑制cAMP外流则大大减弱和的表达。重要的是，注射cAMP可改善禁食小鼠和肥胖小鼠的脂质稳态，而抑制cAMP外流则会加剧禁食小鼠的肝脏脂肪变性。总体而言，我们的结果表明胰高血糖素刺激的细胞外cAMP在通过AMPK介导的PPARα激活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肝脏脂肪变性的潜在新工具。
