Miglustat, a glucosylceramide synthase inhibitor, mitigates liver fibrosis through TGF-β/Smad pathway suppression in hepatic stellate cells

• DOI: 10.1016/j.bbrc.2022.12.025
• Publication Date: 2022-12-10T23:20:50Z
• Authors: Terunao Iwanaga; Tetsuhiro Chiba; Masato Nakamura; Tatsuya Kaneko; Junjie Ao; Na Qiang; Yaojia Ma; Jiaqi Zhang; Tadayoshi Kogure; Sae Yumita; Takamasa Ishino; Keita Ogawa; Motoyasu Kan; Miyuki Nakagawa; Kisako Fujiwara; Naoto Fujita; Takafumi Sakuma; Hiroaki Kanzaki; Keisuke Koroki; Yuko Kusakabe; Masanori Inoue; Kazufumi Kobayashi; Naoya Kanogawa; Soichiro Kiyono; Takayuki Kondo; Ryo Nakagawa; Sadahisa Ogasawara; Shingo Nakamoto; Ryosuke Muroyama; Jun Kato; Tatsuo Kanda; Hitoshi Maruyama; Naoya Mimura; Takuya Honda; Toshihiko Murayama; Hiroyuki Nakamura; Naoya Kato
• Keywords: Liver Cirrhosis; 0301 basic medicine; Smad Proteins; 3. Good health; Mice, Inbred C57BL; Transforming Growth Factor beta1; Mice; 03 medical and health sciences; Liver; Transforming Growth Factor beta; Hepatic Stellate Cells; Animals; Humans; Carbon Tetrachloride; Signal Transduction

Transforming growth factor (TGF)-β/Smad pathway is implicated in the pathogenesis of liver fibrosis, a condition characterized by excessive deposition of extracellular matrix (ECM) proteins such as collagen in response to chronic inflammation. It has been reported that ceramide regulates collagen production through TGF-β/Smad pathway activation. In this study, we examined whether miglustat, an inhibitor of glucosylceramide synthase, can suppress liver fibrosis by reducing TGF-β/Smad pathway activity. Human hepatic stellate cells (HHSteCs) were cultured with TGF-β and multiple miglustat concentrations to examine dose-dependent effects on the expression levels of ECM-related genes and Smad proteins. To evaluate the efficacy of miglustat for fibrosis mitigation, C57BL/6 mice were treated with carbon tetrachloride (CCl4) for 4 weeks to induce liver fibrosis, followed by combined CCl4 plus miglustat for a further 2 weeks. To examine if miglustat can also prevent fibrosis, mice were treated with CCl4 for 2 weeks, followed by CCl4 plus miglustat for 2 weeks. Miglustat dose-dependently downregulated expression of α-smooth muscle actin and ECM components in TGF-β-treated HHSteCs. Both phosphorylation and nuclear translocation of Smad2 and Smad3 were also suppressed by miglustat treatment. Sirius-Red staining and hydroxyproline assays of model mouse liver samples revealed that miglustat reduced fibrosis, an effect accompanied by decreased expression of ECM. Our findings suggest that miglustat can both prevent and reverse liver fibrosis by inhibiting TGF-β/Smad pathway.