J Clin Invest. 2023 Apr 3;133(7):e163508. doi: 10.1172/JCI163508.
The nonessential amino acid asparagine can only be synthesized de novo by the enzymatic activity of asparagine synthetase (ASNS). While ASNS and asparagine have been implicated in the response to numerous metabolic stressors in cultured cells, the in vivo relevance of this enzyme in stress-related pathways remains unexplored. Here, we found ASNS to be expressed in pericentral hepatocytes, a population of hepatic cells specialized in xenobiotic detoxification. ASNS expression was strongly enhanced in 2 models of acute liver injury: carbon tetrachloride (CCl4) and acetaminophen. We found that mice with hepatocyte-specific Asns deletion were more prone to pericentral liver damage than their control littermates after toxin exposure. This phenotype could be reverted by i.v. administration of asparagine. Unexpectedly, the stress-induced upregulation of ASNS involved an ATF4-independent, noncanonical pathway mediated by the nuclear receptor, liver receptor homolog 1 (LRH-1; NR5A2). Altogether, our data indicate that the induction of the asparagine-producing enzyme ASNS acts as an adaptive mechanism to constrain the necrotic wave that follows toxin administration and provide proof of concept that i.v. delivery of asparagine can dampen hepatotoxin-induced pericentral hepatocellular death.
非必需氨基酸天冬酰胺只能通过天冬酰胺合成酶 (ASNS) 的酶活性从头合成。虽然 ASNS 和天冬酰胺已被牵连到培养细胞中许多代谢应激的反应中，但这种酶在应激相关途径中的体内相关性仍未得到探索。在这里，我们发现 ASNS 在中央型肝细胞中表达，中央型肝细胞是一种专门从事外来物解毒的肝细胞。在两种急性肝损伤模型中：四氯化碳 (CCl4) 和对乙酰氨基酚，ASNS 的表达得到了强烈增强。我们发现，与对照同窝仔相比，肝细胞特异性 Asns 缺失的小鼠在毒素暴露后更容易发生中央型肝损伤。这种表型可以通过静脉内给予天冬酰胺来逆转。出乎意料的是，ASNS 的应激诱导上调涉及一种由核受体肝受体同源物 1 (LRH-1; NR5A2) 介导的非典型、ATF4 非依赖性非典型途径。总的来说，我们的数据表明，产生天冬酰胺的酶 ASNS 的诱导是一种适应性机制，可以限制毒素给药后发生的坏死波，并为静脉内给予天冬酰胺可以抑制肝毒素诱导的中央型肝细胞死亡提供了概念验证。
