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

• Published in: Biochemical and biophysical research communications Vol. 642; pp. 192 - 200
• Main Authors: Iwanaga, Terunao, Chiba, Tetsuhiro, Nakamura, Masato, Kaneko, Tatsuya, Ao, Junjie, Qiang, Na, Ma, Yaojia, Zhang, Jiaqi, Kogure, Tadayoshi, Yumita, Sae, Ishino, Takamasa, Ogawa, Keita, Kan, Motoyasu, Nakagawa, Miyuki, Fujiwara, Kisako, Fujita, Naoto, Sakuma, Takafumi, Kanzaki, Hiroaki, Koroki, Keisuke, Kusakabe, Yuko, Inoue, Masanori, Kobayashi, Kazufumi, Kanogawa, Naoya, Kiyono, Soichiro, Kondo, Takayuki, Nakagawa, Ryo, Ogasawara, Sadahisa, Nakamoto, Shingo, Muroyama, Ryosuke, Kato, Jun, Kanda, Tatsuo, Maruyama, Hitoshi, Mimura, Naoya, Honda, Takuya, Murayama, Toshihiko, Nakamura, Hiroyuki, Kato, Naoya
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 29-01-2023
• Subjects: Animals; Carbon Tetrachloride - pharmacology; Glucosylceramide synthase inhibitor; Hepatic Stellate Cells - metabolism; Humans; Liver - metabolism; Liver Cirrhosis - chemically induced; Liver Cirrhosis - drug therapy; Liver Cirrhosis - metabolism; Liver fibrosis; Mice; Mice, Inbred C57BL; Miglustat; Signal Transduction; Smad Proteins - metabolism; TGF-β/Smad pathway; Transforming Growth Factor beta - metabolism; Transforming Growth Factor beta1 - metabolism; Liver fibrosis; Miglustat; Glucosylceramide synthase inhibitor; TGF-β/Smad pathway
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2022.12.025

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.
•Miglustat inhibits phosphorylation and nuclear translocation of Smad2 and Smad3 in hepatic stellate cells.•Downregulation of α-SMA and ECM components are observed after miglustat treatment both in culture and in vivo experiments.•Miglustat prevents and ameliorates liver fibrosis in CCl4-induced liver fibrosis mouse model.