Loss of Urat1 exacerbates APAP-induced liver injury in mice

Acetaminophen (APAP) overdose stands as the paramount contributor to drug-elicited liver damage in clinical settings. Despite this, the intricate interplay between uric acid (UA) levels, its metabolism-linked regulatory genes, and their effects on APAP metabolism and hepatic functions remains elusive. Our study sheds light on this nexus, uncovering that uric acid concentrations and urate transporter-1 (URAT1) expression are intricately intertwined in APAP-induced hepatotoxicity. Notably, elevated serum uric acid levels concomitant with a marked downregulation of hepatic URAT1 expression were discernible in APAP-mediated liver injury models. We also found that high UA exacerbated APAP-induced liver injury in vitro and in vivo. To delve deeper, we devised genetic knockout mice models, specifically targeting URAT1, to unravel its pivotal role in this pathological process. Strikingly, Urat1 knockout (Urat1-/-) mice exhibited exacerbated APAP-triggered hepatotoxicity when juxtaposed against their genetically intact wild-type (Urat1+/+) counterparts, accompanied by increased serum and hepatic UA contents. However, the changes in UA levels might not be the only factor exacerbating APAP liver injury in Urat1-/- mice, as Urat1 knockout has also been proved to affect many other metabolites associated with the redox homeostasis. Mechanistically, we found that the ablation of Urat1 not only intensified triglyceride accumulation instigated by APAP via inhibiting PPAR-alpha pathway but also ignited the NLRP3/NF-kappa B and JNK/ERK signaling cascades, and disrupted oxidative stress homeostasis via downregulating KEAP1/NRF2 pathway. Collectively, our findings underscore that URAT1 acts as a multifaceted facilitator of APAP-induced liver injury in mice, thereby positioning it as a genetic vulnerability factor in APAP overdose scenarios.