Argininosuccinate synthetase regulates hepatic AMPK linking protein catabolism and ureagenesis to hepatic lipid metabolism
Argininosuccinate synthetase regulates hepatic AMPK linking protein catabolism and ureagenesis to hepatic lipid metabolism
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DOI：
10.1073/pnas.1606022113
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发表时间：
2016-06-14
影响因子：
11.1
通讯作者：
Shulman, Gerald I.
中科院分区：
文献类型：
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作者：
Madiraju, Anila K.;Alves, Tiago;Shulman, Gerald I.
细胞能量状态的关键传感器，AMP激活的蛋白激酶（AMPK），与AMP变构相互作用以维持活性状态。当AMPK活跃时，它会触发代谢开关，降低合成代谢途径的活性，增强分解代谢过程，如脂质氧化，以恢复能量平衡。与氧化组织不同，其中AMP在高能量需求状态期间由腺苷酸激酶产生，鸟氨酸循环酶氨基琥珀酸合成酶（ASS）是肝脏中AMP产生的主要位点。在这里，我们表明，ASS调节肝脏AMPK，揭示了通过AMPK调节代谢的尿素生成通量的核心作用。用氨基酸处理原代大鼠肝细胞增加了肝细胞再生和尿素生成，尽管营养过剩，但诱导AMPK和乙酰辅酶A羧化酶（ACC）磷酸化。反义寡核苷酸在体内敲低肝脏ASS 1表达可降低肝脏AMPK活化、ACC磷酸化和血浆β-羟基丁酸浓度。总之，这些研究表明，增加的氨基酸流量可以通过增加ASS产生的AMP激活AMPK，从而提供了蛋白质催化剂，尿素生成和肝脏脂质代谢之间的新联系。
A key sensor of cellular energy status, AMP-activated protein kinase (AMPK), interacts allosterically with AMP to maintain an active state. When active, AMPK triggers a metabolic switch, decreasing the activity of anabolic pathways and enhancing catabolic processes such as lipid oxidation to restore the energy balance. Unlike oxidative tissues, in which AMP is generated from adenylate kinase during states of high energy demand, the ornithine cycle enzyme argininosuccinate synthetase (ASS) is a principle site of AMP generation in the liver. Here we show that ASS regulates hepatic AMPK, revealing a central role for ureagenesis flux in the regulation of metabolism via AMPK. Treatment of primary rat hepatocytes with amino acids increased gluconeogenesis and ureagenesis and, despite nutrient excess, induced both AMPK and acetyl-CoA carboxylase (ACC) phosphorylation. Antisense oligonucleotide knockdown of hepatic ASS1 expression in vivo decreased liver AMPK activation, phosphorylation of ACC, and plasma beta-hydroxybutyrate concentrations. Taken together these studies demonstrate that increased amino acid flux can activate AMPK through increased AMP generated by ASS, thus providing a novel link between protein catabolism, ureagenesis, and hepatic lipid metabolism.