Asparagine protects pericentral hepatocytes during acute liver injury

Abstract

The non-essential 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 two models of acute liver injury: carbon tetrachloride (CCl 4 ) and acetaminophen (APAP). We found that mice with hepatocyte-specific Asns deletion (Asns hep-/-) were more prone to pericentral liver damage than their control (Asns hep+/+ ) littermates after toxin exposure. This phenotype could be reverted by intravenous administration of asparagine. Unexpectedly, the stress-induced upregulation of ASNS involved an ATF4-independent, non-canonical 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 intravenous delivery of asparagine can dampen hepatotoxininduced pericentral hepatocellular death.

LRH-1 induces hepatoprotective nonessential amino acids in response to acute liver injury

“…Indeed, in the field of cancer metabolism, asparagine has been recognized as a proproliferative factor secondary to its role as an amino acid exchange factor, whereby intracellular asparagine export results in serine/threonine uptake, mTORC1 activation, and coordinated protein and nucleotide synthesis ( 12 ). The results by Sun, et al ( 10 ) warrant a renewed interest in asparagine and the mechanisms by which it induces a prosurvival hepatocyte program.…”

“…In contrast, only a limited body of literature has investigated factors that prevent hepatocyte cell death prior to hepatocyte proliferation, providing limited insight into physiologically relevant stress responses and potential therapeutic avenues for acute liver injury management ( 6 – 9 ). In this issue of the JCI , Sun, et al advance our understanding of such prosurvival signals in response to hepatocyte injury, delineating a mechanism by which hepatocyte activation of the nuclear receptor liver receptor homolog-1 (LRH-1) rewires metabolic networks to drive asparagine synthesis from glutamine, a process that limits the extent of hepatocellular death and liver injury without affecting proliferation ( 10 ).…”

“…Since genetic ablation of hepatic ASNS alone could not indicate the relative impact of either depletion of substrate or generation of product, Sun et al confirmed, via amino acid profiling and evaluating the consequences of i.v. injection, that the ASNS product asparagine, but not glutamate or valine, was indeed the protective metabolite ( 10 ).…”

“…Sun and colleagues focused their experimental work on acute hepatotoxic injury models in mice, but also raised the prospect of broader translation by identifying increased ASNS expression in human cohorts of pharmaceutical, environmental, and viral hepatic injury that suggest induction of asparagine as a potential common hepatoprotective response to hepatic stressors ( 10 ). Collectively, these results build on several emerging areas of metabolic biology worth highlighting.…”

“…Prior to the investigation by Sun et al, little was known about cellular signaling roles of the nonessential amino acid asparagine, apart from early observations that asparagine inhibits autophagic protein breakdown via lysosomal delivery ( 11 ). The results by Sun et al raise provocative questions about how asparagine exerts its hepatoprotective effects ( 10 ). Asparagine’s effects may be direct, through autophagy-related or currently unrecognized prosurvival effects, or they may be indirect.…”