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Hassan Reda Hassan Elsayed1, Mohammad El-Nablaway2, Basma H Othman3
1Department of Anatomy and Embryology, Faculty of Medicine, Mansoura University, Egypt.
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.
Insights
Dasatinib, a tyrosine kinase inhibitor, shows promise in treating Non-alcoholic steatohepatitis (NASH) by reducing liver damage and inflammation. This study found Dasatinib effectively ameliorates NASH progression in mice, offering a potential new therapeutic avenue.
Area of Science:
- Hepatology and Pharmacology
- Investigational drug efficacy in metabolic liver disease
Background:
- Non-alcoholic fatty liver disease (NAFLD) is a global health concern, with its progressive form, Non-alcoholic steatohepatitis (NASH), lacking effective treatments.
- Dasatinib, a tyrosine kinase inhibitor with known anti-PDGFR activity and macrophage modulation capabilities, was investigated for its potential therapeutic effects on NASH.
Purpose of the Study:
- To evaluate the efficacy of Dasatinib in ameliorating the pathological features of Non-alcoholic steatohepatitis (NASH) induced in a mouse model.
- To explore the molecular mechanisms underlying Dasatinib's effects on lipogenesis, inflammation, and fibrosis in NASH.
Main Methods:
- NASH was induced in C57BL/6 mice using a Western Diet (WD).
- Mice were treated with Dasatinib (4 mg/kg or 8 mg/kg) or vehicle (DMSO) for four weeks.
- Evaluations included serum biochemistry, immunohistochemistry for key markers (SREBP1, macrophage polarization markers, TGF-β, ASMA), gene expression analysis, and western blotting for signaling pathways.
Main Results:
- Dasatinib treatment significantly improved serum ALT and lipid profiles in WD-fed mice.
- The drug reduced hepatic expression of lipogenesis markers (SREBP-1), pro-inflammatory mediators (iNOS, IL1α, COX2), fibrosis markers (TGF-β, ASMA), and PDGFR signaling.
- Dasatinib promoted M2 macrophage polarization (increased arginase-1 and CD163) and attenuated steatosis, inflammation, hepatocellular ballooning, and fibrosis, leading to reduced NAFLD activity scores.
Conclusions:
- Dasatinib effectively prevents the progression of Western Diet-induced NASH in mice.
- The therapeutic effects are attributed to the attenuation of lipogenesis and the induction of M2 macrophage polarization with associated anti-fibrotic activity.
- Dasatinib represents a promising therapeutic candidate for NASH treatment.
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