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

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.

Lipoxygenases in chronic liver diseases: current insights and future perspectives

“…Elevated 5-LOX expression levels are observed in liver tissue of patients with NASH, liver fibrosis, ALD-induced cirrhosis, and HCC [22][23][24]. 5-LOX expression was also upregulated in several experimental models including hyperlipidemia-prone apolipoprotein E-deficient (ApoE −/− ) mice, high-fat diet (HFD)-and methionine/choline-deficient (MCD) diet-induced steatosis, inflammation, and fibrosis, as well as in carbon tetrachloride (CCl 4 )-induced liver fibrosis and diethylnitrosamine (DEN)-induced HCC [22,23,25,26]. In liver, 5-LOX is expressed in (resident) liver macrophages, hepatocytes, and HSCs [22].…”

“…5-LOX expression was also upregulated in several experimental models including hyperlipidemia-prone apolipoprotein E-deficient (ApoE −/− ) mice, high-fat diet (HFD)-and methionine/choline-deficient (MCD) diet-induced steatosis, inflammation, and fibrosis, as well as in carbon tetrachloride (CCl 4 )-induced liver fibrosis and diethylnitrosamine (DEN)-induced HCC [22,23,25,26]. In liver, 5-LOX is expressed in (resident) liver macrophages, hepatocytes, and HSCs [22]. Genetic ablation of Alox5 reduced paracetamol and acetaminophen (APAP)-induced liver injury [27][28][29], protected against endotoxin-induced liver injury/dysfunction [30], alleviated MCD-and CCl 4 -induced liver fibrosis [22], and protected against HFD-induced liver injury in rodents [26].…”

“…In liver, 5-LOX is expressed in (resident) liver macrophages, hepatocytes, and HSCs [22]. Genetic ablation of Alox5 reduced paracetamol and acetaminophen (APAP)-induced liver injury [27][28][29], protected against endotoxin-induced liver injury/dysfunction [30], alleviated MCD-and CCl 4 -induced liver fibrosis [22], and protected against HFD-induced liver injury in rodents [26]. This is attributed to reduced production of proinflammatory 5-LOX metabolites including LTB4 and LTD4 (and 5-HETE) [22,26].…”

Discovery of a Potent and Orally Active Dual GPBAR1/CysLT1R Modulator for the Treatment of Metabolic Fatty Liver Disease

“…Among the several targets, the cysteinyl leukotriene receptor 1 (CysLT 1 R) and the bile acid receptor GPBAR1 have been shown to be involved in disease development in several animal models of NAFLD/NASH. Of relevance, CysLT 1 R and GPBAR1 are expressed by the liver resident macrophages, the Kupffer cells ( Keitel et al, 2007 ; Keitel et al, 2008 ; Fiorucci and Distrutti 2019 ; Fiorucci et al, 2021 ), and the HSC ( Huber et al, 1989 ; Uemura et al, 1994 ; Clària et al, 1998 ; Horrillo et al, 2007 ; El-Swefy and Hassanen 2009 ; Kurtoğlu et al, 2019 ; Pu et al, 2021 ). Activation of these receptors in Kupffer cells promotes opposite effects.…”

Long Noncoding RNA Metastasis-Associated Lung Adenocarcinoma Transcript 1 in Extracellular Vesicles Promotes Hepatic Stellate Cell Activation, Liver Fibrosis and β-Catenin Signaling Pathway

“…Liver fibrosis is a long-term pathological process characterized by increased extracellular matrix (ECM) around the liver parenchyma ( Ellis and Mann, 2012 ). It often occurs in response to a variety of hepatic insults such as metabolic abnormalities, hepatitis B/C virus infections, toxins, drugs, and etc., ( Pu et al, 2021 ). When an insult induces a liver injury, the parenchymal cells regenerate to replace the injured hepatic cells.…”