Inhibiting Hepatocyte Uric Acid Synthesis and Reabsorption Ameliorates Acetaminophen-Induced Acute Liver Injury in Mice

作者：Chenxi Tang, Cen Li, Hang Zeng, Xiaofen Zhang, Peihao Liu, Yishu Chen, Xin Song, Bingru Lin, Xuequn Zhang, Chaohui Yu, Chengfu Xu · 发表于：Cellular and Molecular Gastroenterology and Hepatology · 年份：2023 · DOI：10.1016/j.jcmgh.2023.10.005 · 被引用次数：13 · 研究领域：Gout, Hyperuricemia, Uric Acid、Drug-Induced Hepatotoxicity and Protection、Alcohol Consumption and Health Effects

BACKGROUND & AIMS: Acetaminophen (APAP) overdose is the most common cause of drug-induced liver injury worldwide. Uric acid (UA) is involved in sterile inflammation in many organs, but its role in APAP-induced liver injury remains elusive. METHODS: We quantified the concentration of UA in the serum and liver tissues of APAP-overdosed mice and explored the changes in proteins involved in UA synthesis, absorption, and degeneration on APAP stimulation. We also examined the effects of inhibiting hepatocyte UA synthesis or reabsorption on APAP-induced liver injury in mice. Furthermore, we explored the process of UA clearance by peripheral macrophages. RESULTS: APAP overdose significantly increased intrahepatic UA contents, which occurred earlier than apparent hepatocyte injury in APAP-overdosed mice. APAP overdose induced significant DNA leakage and may thereby increase the substrate of UA synthesis. APAP overdose also significantly increased the enzymatic activity of xanthine oxidase and urate oxidase and decreased the expression of the UA reabsorption transporter GLUT9 in hepatocytes. Inhibiting hepatocyte UA synthesis by febuxostat or reabsorption by hepatic-specific knockout of GLUT9 alleviated APAP-induced liver injury. Further experiments showed that monosodium urate but not soluble UA may be a major form of UA mediating hepatocyte injury. Additionally, monosodium urate further recruited circulating macrophages into the liver and then aggravated inflammation by increasing th...