Dissecting the role of the asparagine synthesis in acute liver injury

Amino acids are some of the main building stones of life used in a variety of biological processes, such as protein synthesis, energy metabolism or even as precursors for hormone synthesis. How-ever, some of them also participate and coordinate certain cellular functions through unknown mechanisms. Essential amino acids need to be acquired from food, while nonessential amino ac-ids can be synthesized from metabolic intermediates. The nonessential amino acid asparagine can only be synthetized 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. Pericentral hepatocytes are specialized in xenobiotic detoxification. As such, these hepatic cells find themselves at high risk of toxin exposure and are particularly susceptible to cell death. In this thesis, we demonstrated that ASNS is majorly expressed in pericentral hepatocytes and that its expression is strongly enhanced in two models of acute liver injury: carbon tetrachloride (CCl4) and acetaminophen (APAP). We found that mice with a hepatocyte-specific Asns deletion (Asnshep-/-) were more prone to cell death and liver damage than their control (Asnshep+/+) littermates after toxin exposure. Importantly, acute supplementation with asparagine, the product of ASNS, is suf-ficient to dampen pericentral damage during acute liver injury. Unexpectedly, the stress-induced upregulation of ASNS involves an ATF4-independent, non-canonical pathway, mediated by the nuclear receptor, liver receptor homolog 1 (LRH-1). Accordingly, various genetically engineered mouse models were used to reveal that modulation of hepatic LRH-1 activity alters the expression of hepatic ASNS and the susceptibility of pericentral hepatocytes to necrosis. 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 pro-vide proof-of-concept that intravenous delivery of asparagine dampens hepatotoxin-induced peri-central hepatocellular death. These observations provide new therapeutic opportunities to allevi-ate drug-induced hepatotoxicity in humans.