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

**Background:** Acute hepatic injury occurs in response to various stressors including trauma, hepatotoxins, and hepatitis. While extensive research has characterized signals required for hepatocyte proliferation and liver regeneration, much less is known about endogenous prosurvival programs that limit hepatocyte death in the immediate aftermath of injury. The nuclear receptor liver receptor homolog-1 (LRH-1; NR5A2) has established roles in metabolic regulation but its function in acute injury responses has been underexplored. Amino acids, long considered passive metabolic substrates, are increasingly recognized as active signaling molecules that influence cell fate.

**Methods:** Sun and colleagues used multiple complementary mouse models to investigate the LRH-1–ASNS–asparagine axis in acute liver injury. They employed sublethal dosing of carbon tetrachloride (CCl4) and acetaminophen to induce acute hepatotoxic injury. Genetic models included hepatic LRH-1 knockout mice, LRH-1 gain-of-function models (activating K289R point mutation and hepatic SHP knockout, where SHP is a negative regulator of LRH-1), and hepatic ASNS knockout mice. The authors performed ChIP and cotransfection assays to confirm direct LRH-1 binding to the ASNS promoter. Amino acid profiling and intravenous injection experiments were used to identify asparagine as the protective metabolite. Human translational relevance was assessed by examining ASNS expression in cohorts with pharmaceutical, environmental, and viral hepatic injury.

**Key Results:** The authors made the initial observation that hepatocytes expressing GLUL (glutamine synthetase) also expressed ASNS but lacked glutaminase, revealing cellular-level compartmentalization of glutamine metabolism. ASNS was maximally induced 24 hours after sublethal CCl4 or acetaminophen administration. Genetic ablation of hepatic ASNS enhanced liver damage in both injury models, confirming the adaptive nature of this response. Notably, ASNS induction was not mediated through classical stress pathways like ATF4 but through LRH-1 activity. Hepatic LRH-1 knockout mice exhibited low ASNS expression and increased damage following chemically induced injury. Conversely, both LRH-1 gain-of-function models (K289R mutation and SHP knockout) showed upregulated ASNS expression and substantial protection from hepatic injury. ChIP and cotransfection assays confirmed direct LRH-1 binding to the ASNS promoter with increased transcriptional activity. Through amino acid profiling and intravenous injection experiments, the authors confirmed that asparagine itself—not glutamate or valine—was the protective metabolite. Importantly, increased ASNS expression was also identified in human cohorts with pharmaceutical, environmental, and viral hepatic injury, suggesting this may represent a conserved hepatoprotective response.

**Clinical Implications:** This work identifies a previously unrecognized endogenous hepatoprotective program in which LRH-1 activation drives de novo asparagine synthesis to limit acute liver injury. The finding raises the possibility that asparagine supplementation could be a therapeutic strategy for acute hepatic injury, though the authors note that asparagine is absent from most parenteral amino acid solutions. The study also prompts investigation into whether glutamine, which is readily available as a stable dipeptide formulation and serves as a substrate for asparagine synthesis, could substitute for asparagine in inducing hepatoprotection. The coexpression of ASNS and LRH-1 in other injury-prone tissues such as the pancreas suggests broader relevance beyond the hepatocyte. Key open questions include the mechanisms by which asparagine promotes cell survival, whether hepatocytes sense cellular asparagine levels, the upstream signals that induce LRH-1 activity upon injury, and whether LRH-1 ligands could play a therapeutic role in acute hepatic injury.