AUTHOR=Pu Shiyun , Li Yanping , Liu Qinhui , Zhang Xu , Chen Lei , Li Rui , Zhang Jinhang , Wu Tong , Tang Qin , Yang Xuping , Zhang Zijing , Huang Ya , Kuang Jiangying , Li Hong , Zou Min , Jiang Wei , He Jinhan
TITLE=Inhibition of 5-Lipoxygenase in Hepatic Stellate Cells Alleviates Liver Fibrosis
JOURNAL=Frontiers in Pharmacology
VOLUME=12
YEAR=2021
URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.628583
DOI=10.3389/fphar.2021.628583
ISSN=1663-9812
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 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.