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-
(fibrosis marker) and ASMA (a marker for activated hepatic stellate cell), hepatic mRNA expression for
SREBP-1, iNOS, arginase-1, TGF- and PDGFA genes; and western blotting for phosphorylated PDGFR
and , SREBP1, iNOS, arginase-1, IL1, COX2, TGF- 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 and , IL1, COX2, SREBP-1, iNOS,
CD68, TGF- 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. |
