<i>Sulfatase</i>-2 Regulates Liver Fibrosis through the TGF-β Signaling Pathway
Transforming growth factor-β (TGF-β) activates hepatic stellate cells (HSCs), which drive liver fibrosis via the production and deposition of extracellular matrix (ECM). We aimed to elucidate the mechanistic role of <i>sulfatase</i>-2 (SULF2) in liver fibrosis. To this end, we induced li...
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| Autores principales: | , , , , , |
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| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
MDPI AG
2021
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/cc40c55beceb4fb8940093a3f1e36b86 |
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| Sumario: | Transforming growth factor-β (TGF-β) activates hepatic stellate cells (HSCs), which drive liver fibrosis via the production and deposition of extracellular matrix (ECM). We aimed to elucidate the mechanistic role of <i>sulfatase</i>-2 (SULF2) in liver fibrosis. To this end, we induced liver fibrosis in wild-type (WT) and SULF2 knockout (<i>Sulf2</i>-KO) mice (6–8 weeks-old) via bile duct ligation (BDL), intraperitoneal injection of carbon tetrachloride (CCl<sub>4</sub>) or thioacetamide (TAA). The levels of fibrosis in the liver sections were assessed via Sirius red and Masson’s trichrome staining, immunohistochemistry and immunoblotting for α-smooth muscle actin (α-SMA) and hydroxyproline. To evaluate the interaction between TGF-β and SULF2, we transfected human HSCs with scrambled control shRNA and shRNA constructs targeting SULF2 and measured α-SMA expression following treatment with TGF-β1 ligand. We show here that knockout of SULF2 significantly decreases collagen content, as well as bands of bridging fibrosis, as demonstrated by Sirius red, Masson’s trichrome and α-SMA staining after BDL, CCl<sub>4</sub> and TAA injection in <i>Sulf2</i>-KO versus WT mice. In all three models of liver fibrosis, we observed significantly lower levels of hydroxyproline in the <i>Sulf2</i>-KO mice compared to the WT mice. HSCs with reduced levels of SULF2 failed to significantly express α-SMA and collagen type I following treatment with TGF-β1. Furthermore, SULF2 co-localizes with TGFBR3 and the in vitro knockdown of SULF2 in HSCs decreases the release of TGF-β1 from TGFBR3. Together, these data suggest that SULF2 regulates liver fibrosis via the TGF-β signaling pathway. Pharmacologic inhibition of SULF2 may represent a novel therapeutic approach to improve liver fibrosis. |
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