Hyperuricemia induces liver injury by upregulating HIF-1? and inhibiting arginine biosynthesis pathway in mouse liver and human L02 hepatocytes

The molecular mechanisms of uric acid (UA)-induced liver injury has not been clearly elucidated. In this study, we aimed to investigate the effect and action mechanisms of UA in liver injury. We analyzed the damaging effect of UA on mouse liver and L02 cells and subsequently performed metabolomics studies on L02 cells to identify abnormal metabolic pathways. Finally, we verified transcription factors that regulate related metabolic enzymes. UA directly activated the hepatic NLRP3 inflammasome and Bax apoptosis pathway in vivo and in vitro. Related metabolites in the arginine biosynthesis pathway (or urea cycle), L-arginine and L-argininosuccinate were decreased, and ammonia was increased in UA-stimulated L02 cells, which was mediated by carbamoyl phosphate synthase 1 (CPS1), argininosuccinate synthase (ASS) and argininosuccinate lyase (ASL) downregulation. UA upregulated hypoxia inducible factor-1alpha (HIF-1a) in vivo and in vitro, and HIF-1a inhibition alleviated the UA-induced ASS downregulation and hepatocyte injury. In conclusion, UA upregulates HIF-1a and inhibits urea cycle enzymes (UCEs). This leads to liver injury, with evidence of hepatocyte inflammation, apoptosis and oxidative stress. (c) 2022 Elsevier Inc. All rights reserved.

Automated summary

The molecular mechanisms of uric acid-induced liver injury have not been fully understood. This study revealed that uric acid directly activates inflammation and apoptosis pathways in liver cells, while inhibiting urea cycle enzymes. The upregulation of hypoxia inducible factor-1α by uric acid plays a role in these processes.