Frontiers in Pharmacology (Feb 2021)

Inhibition of 5-Lipoxygenase in Hepatic Stellate Cells Alleviates Liver Fibrosis

  • Shiyun Pu,
  • Shiyun Pu,
  • Yanping Li,
  • Qinhui Liu,
  • Xu Zhang,
  • Lei Chen,
  • Lei Chen,
  • Rui Li,
  • Rui Li,
  • Jinhang Zhang,
  • Jinhang Zhang,
  • Tong Wu,
  • Tong Wu,
  • Qin Tang,
  • Qin Tang,
  • Xuping Yang,
  • Xuping Yang,
  • Zijing Zhang,
  • Zijing Zhang,
  • Ya Huang,
  • Ya Huang,
  • Jiangying Kuang,
  • Jiangying Kuang,
  • Hong Li,
  • Hong Li,
  • Min Zou,
  • Wei Jiang,
  • Jinhan He,
  • Jinhan He

DOI
https://doi.org/10.3389/fphar.2021.628583
Journal volume & issue
Vol. 12

Abstract

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Background and Purpose: Activation of hepatic stellate cells (HSC) is a central driver of liver fibrosis. 5-lipoxygenase (5-LO) is the key enzyme that catalyzes arachidonic acid into leukotrienes. In this study, we examined the role of 5-LO in HSC activation and liver fibrosis.Main Methods: Culture medium was collected from quiescent and activated HSC for target metabolomics analysis. Exogenous leukotrienes were added to culture medium to explore their effect in activating HSC. Genetic ablation of 5-LO in mice was used to study its role in liver fibrosis induced by CCl4 and a methionine-choline-deficient (MCD) diet. Pharmacological inhibition of 5-LO in HSC was used to explore the effect of this enzyme in HSC activation and liver fibrosis.Key Results: The secretion of LTB4 and LTC4 was increased in activated vs. quiescent HSC. LTB4 and LTC4 contributed to HSC activation by activating the extracellular signal-regulated protein kinase pathway. The expression of 5-LO was increased in activated HSC and fibrotic livers of mice. Ablation of 5-LO in primary HSC inhibited both mRNA and protein expression of fibrotic genes. In vivo, ablation of 5-LO markedly ameliorated the CCl4- and MCD diet-induced liver fibrosis and liver injury. Pharmacological inhibition of 5-LO in HSC by targeted delivery of the 5-LO inhibitor zileuton suppressed HSC activation and improved CCl4- and MCD diet-induced hepatic fibrosis and liver injury. Finally, we found increased 5-LO expression in patients with non-alcoholic steatohepatitis and liver fibrosis.Conclusion: 5-LO may play a critical role in activating HSC; genetic ablation or pharmacological inhibition of 5-LO improved CCl4-and MCD diet-induced liver fibrosis.

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