Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Basel, Switzerland.
Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland.
Sci Rep. 2018 Oct 17;8(1):15331. doi: 10.1038/s41598-018-32853-w.
Macrophages have been recognized as key players in non-alcoholic fatty liver disease (NAFLD). Our aim was to assess whether pharmacological attenuation of macrophages can be achieved by imatinib, an anti-leukemia drug with known anti-inflammatory and anti-diabetic properties, and how this impacts on NAFLD. We analyzed the pro- and anti-inflammatory gene expression of murine macrophages and human monocytes in vitro in the presence or absence of imatinib. In a time-resolved study, we characterized metabolic disease manifestations such as hepatic steatosis, systemic and adipose tissue inflammation as well as lipid and glucose metabolism in obese mice at one and three months of imatinib treatment. Our results showed that imatinib lowered pro-inflammatory markers in murine macrophages and human monocytes in vitro. In obese mice, imatinib reduced TNFα-gene expression in peritoneal and liver macrophages and systemic lipid levels at one month. This was followed by decreased hepatic steatosis, systemic and adipose tissue inflammation and increased insulin sensitivity after three months. As the transcription factor sterol regulatory element-binding protein (SREBP) links lipid metabolism to the innate immune response, we assessed the gene expression of SREBPs and their target genes, which was indeed downregulated in the liver and partially in peritoneal macrophages. In conclusion, targeting both inflammatory and lipogenic pathways in macrophages and liver as shown by imatinib could represent an attractive novel therapeutic strategy for patients with NAFLD.
巨噬细胞被认为是非酒精性脂肪性肝病（NAFLD）的关键参与者。我们的目的是评估伊马替尼（一种具有已知抗炎和抗糖尿病特性的抗白血病药物）是否可以通过药理作用来抑制巨噬细胞，并探讨这种作用对 NAFLD 的影响。我们在体外分析了伊马替尼存在或不存在的情况下，小鼠巨噬细胞和人单核细胞的促炎和抗炎基因表达。在一项时间分辨研究中，我们在肥胖小鼠中研究了一个月和三个月伊马替尼治疗后的代谢性疾病表现，如肝脂肪变性、全身和脂肪组织炎症以及脂质和葡萄糖代谢。我们的结果表明，伊马替尼降低了体外小鼠巨噬细胞和人单核细胞中的促炎标志物。在肥胖小鼠中，伊马替尼在一个月时降低了腹腔巨噬细胞和肝脏巨噬细胞中的 TNFα 基因表达以及全身脂质水平。三个月后，肝脂肪变性、全身和脂肪组织炎症减少，胰岛素敏感性增加。由于固醇调节元件结合蛋白（SREBP）将脂质代谢与先天免疫反应联系起来，我们评估了 SREBPs 及其靶基因的基因表达，结果发现肝脏和部分腹腔巨噬细胞中的基因表达下调。总之，伊马替尼对巨噬细胞和肝脏中的炎症和脂质生成途径的靶向作用可能是 NAFLD 患者一种有吸引力的新治疗策略。
