Miglustat, a glucosylceramide synthase inhibitor, mitigates liver fibrosis through TGF-5/Smad pathway suppression in hepatic stellate cells

被引：5

作者：

Iwanaga, Terunao ^{[1
]}

Chiba, Tetsuhiro ^{[1
,7
]}

Nakamura, Masato ^{[1
]}

Kaneko, Tatsuya ^{[1
]}

Ao, Junjie ^{[1
]}

Qiang, Na ^{[1
]}

Ma, Yaojia ^{[1
]}

Zhang, Jiaqi ^{[1
]}

Kogure, Tadayoshi ^{[1
]}

Yumita, Sae ^{[1
]}

Ishino, Takamasa ^{[1
]}

Ogawa, Keita ^{[1
]}

Kan, Motoyasu ^{[1
]}

Nakagawa, Miyuki ^{[1
]}

Fujiwara, Kisako ^{[1
]}

Fujita, Naoto ^{[1
]}

Sakuma, Takafumi ^{[1
]}

Kanzaki, Hiroaki ^{[1
]}

Koroki, Keisuke ^{[1
]}

Kusakabe, Yuko ^{[1
]}

Inoue, Masanori ^{[1
]}

Kobayashi, Kazufumi ^{[1
]}

Kanogawa, Naoya ^{[1
]}

Kiyono, Soichiro ^{[1
]}

Kondo, Takayuki ^{[1
]}

Nakagawa, Ryo ^{[1
]}

Ogasawara, Sadahisa ^{[1
]}

Nakamoto, Shingo ^{[1
]}

Muroyama, Ryosuke ^{[2
]}

Kato, Jun ^{[1
]}

Kanda, Tatsuo ^{[3
]}

Maruyama, Hitoshi ^{[4
]}

Mimura, Naoya ^{[5
]}

Honda, Takuya ^{[6
]}

Murayama, Toshihiko ^{[6
]}

Nakamura, Hiroyuki ^{[6
]}

Kato, Naoya ^{[1
]}

机构：

[1] Chiba Univ, Grad Sch Med, Dept Gastroenterol, Chiba, Japan

[2] Chiba Univ, Grad Sch Med, Dept Mol Virol, Chiba, Japan

[3] Nihon Univ, Dept Med, Div Gastroenterol & Hepatol, Sch Med, Tokyo, Japan

[4] Juntendo Univ, Dept Gastroenterol, Sch Med, Tokyo, Japan

[5] Chiba Univ Hosp, Dept Transfus Med & Cell Therapy, Chiba, Japan

[6] Chiba Univ, Grad Sch Pharmaceut Sci, Lab Chem Pharmacol, Chiba, Japan

[7] Chiba Univ, Grad Sch Med, Dept Gastroenterol, 1-8-1 Inohana,Chuo Ku, Chiba 2608670, Japan

来源：

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS | 2023年 / 642卷

基金：

日本学术振兴会;

关键词：

Miglustat; Glucosylceramide synthase inhibitor; Liver fibrosis; TGF-β Smad pathway; TGF-BETA; SPHINGOSINE; 1-PHOSPHATE; MOLECULAR-MECHANISMS; EXPRESSION; APOPTOSIS; SPHINGOLIPIDS; RESOLUTION; CIRRHOSIS; DEFECTS; MICE;

D O I：

10.1016/j.bbrc.2022.12.025

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Transforming growth factor (TGF)-5/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-5/Smad pathway activation. In this study, we examined whether miglustat, an inhibitor of glucosylceramide synthase, can suppress liver fibrosis by reducing TGF-5/Smad pathway activity. Human hepatic stellate cells (HHSteCs) were cultured with TGF-5 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 a-smooth muscle actin and ECM components in TGF-5-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-5/Smad pathway.(c) 2022 Elsevier Inc. All rights reserved.

引用

页码：192 / 200

页数：9

共 39 条

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