【Background, Purpose】
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, irreversible, and ultimately fatal lung disease. IPF occurs due to TGF-β1/Smad signaling activation.
Previously, we observed that eliglustat, glucosylceramide synthase inhibitor exhibited anti-fibrotic effects against nomal human lung fibroblast. So, we checked whether eliglustat exhibits anti-fibrotic effects also against IPF patient-derived cells (IPF cells), and tried to elucidate its mechanism.
【Results, Discussion】
First, we tested the anti-fibrotic effects of eliglustat in IPF cells. Treatment of IPF cells with eliglustat similarly suppressed the up-regulation of fibrotic proteins such as α-SMA and collagen by TGF-β1. Eliglustat had no effects on phosphorylation and translocation to the nucleus of Smad. The knockdown of glucosylceramide synthase did not inhibit the up-regulation of α-SMA by TGF-β1. These results suggest that eliglustat inhibits fibrotic protein transcription by Smad independently of its inhibitory effect against glucosylceramide synthase. Next, we focused on sterol regulatory element-binding protein2 (SREBP2) to elucidate the anti-fibrotic mechanism of eliglustat. SREBP2 regulates intracellular cholesterol levels and is known to inhibit the transcript activity of Smad. Treatment of IPF cells with eliglustat induced translocation of SREBP2 to the nucleus and up-regulation of downstream genes of SREBP2. Inhibition of SREBP2 attenuated the eliglustat-induced down-regulation of α-SMA expression. These results suggest that eliglustat exhibits anti-fibrotic effects through activation of SREBP2.