Background

Non-alcoholic fatty liver disease (NAFLD) is a worldwide disease that progresses into steatohepatitis (NASH) that has no current effective treatment. This study aimed, for the first time, to investigate the effect of Dasatinib; a tyrosine kinase inhibitor showing anti-PDGFR activity with a macrophage modulating efficacy, on NASH.

Methods

NASH was induced, in C57BL/6 mice by western diet (WD). Control groups received either DMSO or Dasatinib. After 12 weeks, WD-fed mice received DMSO, Dasatinib (4 mg/kg) or Dasatinib (8 mg/kg) once daily, for four weeks. Serum was examined for ALT and lipid profile. Immunohistochemical staining for SREBP1 (lipogenesis marker), iNOS, arginase-1, CD68, CD163 (macrophage polarization markers), TGF-β (fibrosis marker) and ASMA (a marker for activated hepatic stellate cell), hepatic mRNA expression for SREBP-1, iNOS, arginase-1, TGF-β and PDGFA genes; and western blotting for phosphorylated PDGFR α and β, SREBP1, iNOS, arginase-1, IL1α, COX2, TGF-β and ASMA were performed. Liver sections were stained also for H & E, Oil red O and Sirius red.

Results

Dasatinib could ameliorate the WD-induced disturbance of serum ALT, lipid profile and significantly reduced hepatic expression of PDGFA, phosphorylated PDGFR α and β, IL1α, COX2, SREBP-1, iNOS, CD68, TGF-β and ASMA but increased expression for arginase-1 and CD163 (M2 macrophage markers). Moreover, Dasatinib reduced the steatosis, inflammation, hepatocellular ballooning, hepatic fibrosis and the high NAFLD activity scoring induced by WD.

Conclusion

Dasatinib can prevent the progression of WD-induced NASH by attenuating lipogenesis, and inducing M2 macrophage polarization with antifibrotic activity.

中文翻译：

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达沙替尼能否改善由长期西方饮食引起的小鼠肝脏变化？

背景

非酒精性脂肪性肝病 (NAFLD) 是一种全球性疾病，可进展为脂肪性肝炎 (NASH)，目前尚无有效治疗方法。本研究首次旨在调查达沙替尼的作用；一种酪氨酸激酶抑制剂，在 NASH 上显示出具有巨噬细胞调节功效的抗 PDGFR 活性。

方法

通过西方饮食 (WD) 在 C57BL/6 小鼠中诱导 NASH。对照组接受 DMSO 或达沙替尼。12 周后，WD 喂养的小鼠每天一次接受 DMSO、达沙替尼 (4 mg/kg) 或达沙替尼 (8 mg/kg)，持续 4 周。检查血清的 ALT 和脂质谱。SREBP1（脂肪生成标记物）、iNOS、精氨酸酶-1、CD68、CD163（巨噬细胞极化标记物）、TGF-β（纤维化标记物）和 ASMA（活化肝星状细胞标记物）的免疫组织化学染色，SREBP-1 的肝 mRNA 表达, iNOS, arginase-1, TGF-β 和 PDGFA 基因；并对磷酸化的 PDGFR α 和 β、SREBP1、iNOS、精氨酸酶-1、IL1α、COX2、TGF-β 和 ASMA 进行蛋白质印迹。肝脏切片也被染色为 H & E、油红 O 和天狼星红。

结果

达沙替尼可改善 WD 诱导的血清 ALT、血脂谱紊乱，并显着降低肝脏中 PDGFA、磷酸化 PDGFR α 和 β、IL1α、COX2、SREBP-1、iNOS、CD68、TGF-β 和 ASMA 的表达，但增加精氨酸酶的表达-1 和 CD163（M2 巨噬细胞标记物）。此外，达沙替尼减少了由 WD 引起的脂肪变性、炎症、肝细胞气球样变、肝纤维化和高 NAFLD 活动评分。

结论

达沙替尼可以通过减弱脂肪生成和诱导具有抗纤维化活性的 M2 巨噬细胞极化来阻止 WD 诱导的 NASH 的进展。