Inhibition of 5-Lipoxygenase in Hepatic Stellate Cells Alleviates Liver Fibrosis
Shiyun Pu, Yanping Li, Qinhui Liu, Xu Zhang, Lei Chen, Rui Li, Jinhang Zhang, Tong Wu, Qin Tang, Xuping Yang, Zijing Zhang, Ya Huang, Jiangying Kuang, Hong Li, Min Zou, Wei Jiang, Jinhan He
Abstract
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 CCl 4 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 LTB 4 and LTC 4 was increased in activated vs. quiescent HSC. LTB 4 and LTC 4 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 CCl 4 - 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 CCl 4 - 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 CCl 4 -and MCD diet-induced liver fibrosis.