Eliglustat exerts anti-fibrotic effects by activating SREBP2 in TGF-ß1-treated myofibroblasts derived from patients with idiopathic pulmonary fibrosis.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive chronic lung disease. Myofibroblasts play a critical role in fibrosis. These cells produce the extracellular matrix (ECM), which contributes to tissue regeneration; however, excess ECM production can cause fibrosis. Transforming growth factor-ß (TGF-ß)/Smad signaling induces ECM production by myofibroblasts; therefore, the inhibition of TGF-ß/Smad signaling may be an effective strategy for IPF treatment. We recently reported that miglustat, an inhibitor of glucosylceramide synthase (GCS), ameliorates pulmonary fibrosis by inhibiting the nuclear translocation of Smad2/3. In the present study, we examined the anti-fibrotic effects of another GCS inhibitor, eliglustat, a clinically approved drug for treating Gaucher disease type 1, in myofibroblasts derived from patient with IPF (IPF-MyoFs). We found that eliglustat exerted anti-fibrotic effects independent of GCS inhibition, and inhibited TGF-ß1-induced expression of α-smooth muscle actin, a marker of fibrosis, without suppressing the phosphorylation and nuclear translocation of Smad2/3. RNA sequencing analysis of eliglustat-treated human lung fibroblasts identified sterol regulatory element-binding protein 2 (SREBP2) activation. Transient overexpression of SREBP2 attenuated the TGF-ß1-induced increase in the expression of Smad target genes in IPF-MyoFs, and SREBP2 knockdown nullified the inhibitory effect of eliglustat on TGF-ß1-induced expression of α-SMA. These results suggested that eliglustat exerts its anti-fibrotic effects through SREBP2 activation. The findings of this study may contribute to the development of novel therapeutic strategies for IPF treatment.