Departments of Molecular Genetics, Molecular Cell Biology and Electron Microscopy, School of Nutrition and Translational Research in Metabolism (NUTRIM), University of Maastricht; Universiteitssingel 50, ER 6229 ER, Maastricht, The Netherlands.
Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn; Sigmund-Freud-Str. 25, D-53127, Bonn, Germany.
Sci Rep. 2017 Oct 2;7(1):12550. doi: 10.1038/s41598-017-13058-z.
Despite the consistent rise of non-alcoholic steatohepatitis (NASH) worldwide, the mechanisms that govern the inflammatory aspect of this disease remain unknown. Previous research showed an association between hepatic inflammation and lysosomal lipid accumulation in blood-derived hepatic macrophages. Additionally, in vitro findings indicated that lipids, specifically derived from the oxidized low-density lipoprotein (oxLDL) particle, are resistant to removal from lysosomes. On this basis, we investigated whether lysosomal lipid accumulation in blood-derived hepatic macrophages is causally linked to hepatic inflammation and assessed to what extent increasing anti-oxLDL IgM autoantibodies can affect this mechanism. By creating a proof-of-concept mouse model, we demonstrate a causal role for lysosomal lipids in blood-derived hepatic macrophages in mediating hepatic inflammation and initiation of fibrosis. Furthermore, our findings show that increasing anti-oxLDL IgM autoantibody levels reduces inflammation. Hence, therapies aimed at improving lipid-induced lysosomal dysfunction and blocking oxLDL-formation deserve further investigation in the context of NASH.
尽管全球范围内非酒精性脂肪性肝炎 (NASH) 的发病率持续上升，但导致这种疾病炎症的机制仍不清楚。先前的研究表明，肝脏炎症与血液来源的肝巨噬细胞中溶酶体脂质积累之间存在关联。此外，体外研究结果表明，脂质，特别是来自氧化型低密度脂蛋白 (oxLDL) 颗粒的脂质，难以从溶酶体中清除。在此基础上，我们研究了血液来源的肝巨噬细胞中溶酶体脂质积累是否与肝脏炎症有关，并评估了增加抗 oxLDL IgM 自身抗体在多大程度上可以影响这一机制。通过建立一个概念验证的小鼠模型，我们证明了血液来源的肝巨噬细胞中溶酶体脂质在介导肝脏炎症和纤维化启动中起因果作用。此外，我们的研究结果表明，增加抗 oxLDL IgM 自身抗体水平可减轻炎症。因此，旨在改善脂质诱导的溶酶体功能障碍和阻断 oxLDL 形成的治疗方法在 NASH 背景下值得进一步研究。
