Coyne Erin, Nie Yilin, Abdurrachim Desiree, Ong Charlene Lin Zhi, Zhou Yongqi, Ali Asad Abu Bakar, Meyers Stacey, Grein Jeff, Blumenschein Wendy, Gongol Brendan, Liu Yang, Hugelshofer Cedric Lorenz, Carballo-Jane Ester, Talukdar Saswata
Merck, South San Francisco, California, United States.
Merck, Singapore, Singapore.
Biochem J. 2023 Nov 28;481(3):177-90. doi: 10.1042/BCJ20230422.
MASH is a prevalent liver disease that can progress to fibrosis, cirrhosis, hepatocellular carcinoma (HCC), and ultimately death, but there are no approved therapies. Leukotriene B4 (LTB4) is a potent pro-inflammatory chemoattractant that drives macrophage and neutrophil chemotaxis, and genetic loss or inhibition of its high affinity receptor, leukotriene B4 receptor 1 (BLT1), results in improved insulin sensitivity and decreased hepatic steatosis. To validate the therapeutic efficacy of BLT1 inhibition in an inflammatory and pro-fibrotic mouse model of MASH and fibrosis, mice were challenged with a choline-deficient, L-amino acid defined high fat diet and treated with a BLT1 antagonist at 30 or 90 mg/kg for 8 weeks. Liver function, histology, and gene expression were evaluated at the end of the study. Treatment with the BLT1 antagonist significantly reduced plasma lipids and liver steatosis but had no impact on liver injury biomarkers or histological endpoints such as inflammation, ballooning, or fibrosis compared to control. Artificial intelligence-powered digital pathology analysis revealed a significant reduction in steatosis co-localized fibrosis in livers treated with the BLT1 antagonist. Liver RNA-seq and pathway analyses revealed significant changes in fatty acid, arachidonic acid, and eicosanoid metabolic pathways with BLT1 antagonist treatment, however, these changes were not sufficient to impact inflammation and fibrosis endpoints. Targeting this LTB4-BLT1 axis with a small molecule inhibitor in animal models of chronic liver disease should be considered with caution, and additional studies are warranted to understand the mechanistic nuances of BLT1 inhibition in the context of MASH and liver fibrosis.
非酒精性脂肪性肝炎（MASH）是一种常见的肝脏疾病，可进展为纤维化、肝硬化、肝细胞癌（HCC），最终导致死亡，但目前尚无获批的治疗方法。白三烯B4（LTB4）是一种强效的促炎趋化因子，可驱动巨噬细胞和中性粒细胞趋化，其高亲和力受体白三烯B4受体1（BLT1）的基因缺失或抑制可改善胰岛素敏感性并减少肝脂肪变性。为了验证BLT1抑制在MASH和纤维化的炎症和促纤维化小鼠模型中的治疗效果，用胆碱缺乏、L-氨基酸定义的高脂肪饮食对小鼠进行攻击，并以30或90mg/kg的剂量用BLT1拮抗剂治疗8周。在研究结束时评估肝功能、组织学和基因表达。与对照组相比，用BLT1拮抗剂治疗可显著降低血脂和肝脂肪变性，但对肝损伤生物标志物或组织学终点如炎症、气球样变或纤维化没有影响。人工智能驱动的数字病理学分析显示，用BLT1拮抗剂治疗的肝脏中，脂肪变性与纤维化共定位显著减少。肝脏RNA测序和通路分析显示，用BLT1拮抗剂治疗后，脂肪酸、花生四烯酸和类花生酸代谢通路有显著变化，然而，这些变化不足以影响炎症和纤维化终点。在慢性肝病动物模型中，使用小分子抑制剂靶向这个LTB4-BLT1轴应谨慎考虑，需要进一步研究以了解在MASH和肝纤维化背景下BLT1抑制的机制细微差别。
