Imatinib reduces non-alcoholic fatty liver disease in obese mice by targeting inflammatory and lipogenic pathways in macrophages and liver.
Imatinib reduces non-alcoholic fatty liver disease in obese mice by targeting inflammatory and lipogenic pathways in macrophages and liver.
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伊马替尼通过靶向巨噬细胞和肝脏中的炎症性和脂肪生成途径来减少肥胖小鼠中的非酒精性脂肪肝病。
DOI：
10.1038/s41598-018-32853-w
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发表时间：
2018-10-17
影响因子：
4.6
通讯作者：
Cavelti-Weder C
中科院分区：
文献类型：
--
作者：
AlAsfoor S;Rohm TV;Bosch AJT;Dervos T;Calabrese D;Matter MS;Weber A;Cavelti-Weder C
巨噬细胞已被公认为非酒精性脂肪肝（NAFLD）的关键参与者。我们的目的是评估是否可以通过伊马替尼（一种具有已知抗炎和抗糖尿病特性的抗白血病药物）实现巨噬细胞的药理学衰减，以及这对NAFLD的影响。我们分析了在体外存在或不存在伊马替尼的情况下，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，我们在伊马替尼治疗1个月和3个月的肥胖小鼠中表征了代谢性疾病的表现，如肝脂肪变性、全身性和脂肪组织炎症以及脂质和葡萄糖代谢。我们的研究结果表明，伊马替尼在体外降低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和肝脏巨噬细胞中TNFα基因的表达以及全身脂质水平。三个月后，肝脏脂肪变性、全身和脂肪组织炎症减少，胰岛素敏感性增加。由于转录因子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SREBP及其靶基因的基因表达，这些基因在肝脏和部分腹腔巨噬细胞中确实下调。总之，靶向巨噬细胞和肝脏中的炎症和脂肪生成途径，如伊马替尼所示，可能是NAFLD患者的一种有吸引力的新治疗策略。
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.
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影响因子：
8.8
作者：
Klawitter, J.;Anderson, N.;Klawitter, J.;Christians, U.;Leibfritz, D.;Eckhardt, S. G.;Serkova, N. J.
通讯作者：
Serkova, N. J.
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.8
作者：
Jiang, CY;Ting, AT;Seed, B
通讯作者：
Seed, B
DOI：
10.1002/hep.29477
发表时间：
2018-05
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Friedman SL;Ratziu V;Harrison SA;Abdelmalek MF;Aithal GP;Caballeria J;Francque S;Farrell G;Kowdley KV;Craxi A;Simon K;Fischer L;Melchor-Khan L;Vest J;Wiens BL;Vig P;Seyedkazemi S;Goodman Z;Wong VW;Loomba R;Tacke F;Sanyal A;Lefebvre E
通讯作者：
Lefebvre E
影响因子：
4.8
作者：
Hagerkvist, Robert;Sandler, Stellan;Welsh, Nils
通讯作者：
Welsh, Nils