白三烯B4受体1 (BLT1)在小鼠肝纤维化模型中不介导疾病进展。

IF 4.4 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Biochemical Journal Pub Date : 2023-11-28 DOI:10.1042/BCJ20230422
Erin Coyne, Yilin Nie, Desiree Abdurrachim, Charlene Lin Zhi Ong, Yongqi Zhou, Asad Abu Bakar Ali, Stacey Meyers, Jeff Grein, Wendy Blumenschein, Brendan Gongol, Yang Liu, Cedric Lorenz Hugelshofer, Ester Carballo-Jane, Saswata Talukdar
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引用次数: 0

摘要

MASH是一种常见的肝脏疾病,可发展为纤维化、肝硬化、肝细胞癌(HCC),并最终导致死亡,但目前尚无批准的治疗方法。白三烯B4 (LTB4)是一种有效的促炎化学引诱剂,可驱动巨噬细胞和中性粒细胞趋化,其高亲和受体白三烯B4受体1 (BLT1)的遗传缺失或抑制可改善胰岛素敏感性和减少肝脂肪变性。为了验证BLT1抑制在炎症和促纤维化小鼠MASH和纤维化模型中的治疗效果,研究人员用胆碱缺乏、l -氨基酸定义的高脂肪饮食刺激小鼠,并用BLT1拮抗剂(30或90 mg/kg)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,BLT1拮抗剂治疗显著降低了血浆脂质和肝脏脂肪变性,但对肝损伤生物标志物或组织学终点(如炎症、水肿或纤维化)没有影响。人工智能驱动的数字病理学分析显示,使用BLT1拮抗剂治疗的肝脏脂肪变性共定位纤维化显著减少。肝脏RNA-seq和途径分析显示,BLT1拮抗剂治疗后,脂肪酸、花生四烯酸和类二十烷代谢途径发生了显著变化,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LTB4-BLT1轴应该谨慎考虑,并且需要进一步的研究来了解在MASH和肝纤维化背景下BLT1抑制的机制细微差别。
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Leukotriene B4 receptor 1 (BLT1) does not mediate disease progression in a mouse model of liver fibrosis.

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.

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来源期刊
Biochemical Journal
Biochemical Journal 生物-生化与分子生物学
CiteScore
8.00
自引率
0.00%
发文量
255
审稿时长
1 months
期刊介绍: Exploring the molecular mechanisms that underpin key biological processes, the Biochemical Journal is a leading bioscience journal publishing high-impact scientific research papers and reviews on the latest advances and new mechanistic concepts in the fields of biochemistry, cellular biosciences and molecular biology. The Journal and its Editorial Board are committed to publishing work that provides a significant advance to current understanding or mechanistic insights; studies that go beyond observational work using in vitro and/or in vivo approaches are welcomed. Painless publishing: All papers undergo a rigorous peer review process; however, the Editorial Board is committed to ensuring that, if revisions are recommended, extra experiments not necessary to the paper will not be asked for. Areas covered in the journal include: Cell biology Chemical biology Energy processes Gene expression and regulation Mechanisms of disease Metabolism Molecular structure and function Plant biology Signalling
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