Can Dasatinib Ameliorate the Hepatic changes, Induced by Long Term Western Diet, in Mice?

Abstract

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.

Keywords: Dasatinib; Liver; Liver fibrosis; Macrophage polarization; Steatohepatitis; Tyrosine kinase inhibitors.