2. Academic Validation
  3. Hyperuricemia induces liver injury by upregulating HIF-1α and inhibiting arginine biosynthesis pathway in mouse liver and human L02 hepatocytes

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

  • Biochem Biophys Res Commun. 2022 Aug 30;617(Pt 2):55-61. doi: 10.1016/j.bbrc.2022.05.096.
Lei Huang 1,  Xinyu He 1,  Wen Peng 2,  Xueqing He 1,  Bei Xu 1,  Hu Xu 1,  Yaoxing Wang 1,  Wenjun Xu 1,  Wentong Chen 1,  Sheng Wang 3,  Lanlan Zhou 4,  Ning Liu 5,  Youzhi Xu 6,  Wenjie Lu 7
Affiliations

Affiliations

  • 1 Basic Medical College, Anhui Medical University, Hefei, 230032, China.
  • 2 Department of Oncology, The People's Hospital of Guizhou Province, Guiyang, 550004, China.
  • 3 Center for Scientific Rrsearch, Anhui Medical University, Hefei, 230032, China.
  • 4 School of Medical Technology and Nursing, Shenzhen Polytechnic, Shenzhen, 518055, China.
  • 5 Basic Medical College, Anhui Medical University, Hefei, 230032, China. Electronic address: [email protected].
  • 6 Basic Medical College, Anhui Medical University, Hefei, 230032, China. Electronic address: [email protected].
  • 7 Basic Medical College, Anhui Medical University, Hefei, 230032, China. Electronic address: [email protected].
PMID: 35696777 DOI: 10.1016/j.bbrc.2022.05.096
Abstract

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 invivo and invitro. 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-1α) invivo and invitro, and HIF-1α inhibition alleviated the UA-induced ASS downregulation and hepatocyte injury. In conclusion, UA upregulates HIF-1α and inhibits urea cycle Enzymes (UCEs). This leads to liver injury, with evidence of hepatocyte inflammation, Apoptosis and oxidative stress.

Keywords

ASS; HIF-1α; Liver injury; Uric acid.

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