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Published on: February 10, 2015
Sja-Let-7 Attenuates Carbon Tetrachloride-Induced Liver Fibrosis in a Mouse Model via Col1α2
Haoran Zhong1,2, Bowen Dong1,2, Danlin Zhu1,2
1National Reference Laboratory for Animal Schistosomiasis, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China.
Abstract:
Liver fibrosis (LF) is a chronic progressive disease with no definitive treatment. The aim of this study was to assess helminth-derived molecules as potential therapeutic targets to prevent or reverse LF. A mouse model of carbon tetrachloride (CCL4)-induced LF was established and sja-let-7 was overexpressed by treatment with a miRNA agomir once per week. After four weeks, serum biochemistry, hepatic hydroxyproline content measurements, liver histology, mRNA expression profiling of fibrotic markers, the dual-luciferase reporter assay, and fluorescence in situ hybridization (FISH) were performed. Administration of the sja-let-7 agomir markedly ameliorated hepatosplenomegaly and reduced the liver hydroxyproline content. Liver histological analysis showed significant reductions in collagen deposition in the sja-let-7 agomir-treated mice. Additionally, the mRNA levels of both pro-fibrotic markers and pro-inflammatory cytokines were diminished after treatment. Furthermore, the dual-luciferase reporter assay and FISH identified the α2 chain of collagen type 1 (Col1α2) as the direct target of sja-let-7. Accordingly, the progression of LF was attenuated by targeting Col1α2 and the TGF-β/Smad signaling pathway.
Insights
Helminth-derived sja-let-7 microRNA shows promise in treating liver fibrosis (LF). Overexpression of sja-let-7 reduced fibrosis markers and collagen deposition in a mouse model, suggesting a new therapeutic avenue.
Area of Science:
- Biochemistry
- Molecular Biology
- Immunology
Background:
- Liver fibrosis (LF) is a chronic, progressive liver disease with limited therapeutic options.
- Helminth-derived molecules are being explored for their immunomodulatory and anti-fibrotic properties.
Purpose of the Study:
- To investigate helminth-derived sja-let-7 microRNA as a potential therapeutic target for preventing or reversing liver fibrosis.
- To elucidate the molecular mechanisms underlying the anti-fibrotic effects of sja-let-7.
Main Methods:
- A carbon tetrachloride (CCl4)-induced mouse model of liver fibrosis was established.
- Sja-let-7 microRNA was overexpressed using a miRNA agomir.
- Analyses included serum biochemistry, hepatic hydroxyproline content, liver histology, mRNA profiling, dual-luciferase reporter assay, and fluorescence in situ hybridization (FISH).
Main Results:
- Sja-let-7 agomir treatment ameliorated hepatosplenomegaly and reduced liver hydroxyproline content.
- Histological analysis revealed decreased collagen deposition in treated mice.
- mRNA levels of pro-fibrotic markers and inflammatory cytokines were significantly diminished.
- Col1α2 was identified as a direct target of sja-let-7, mediating the attenuation of LF via the TGF-β/Smad pathway.
Conclusions:
- Sja-let-7 microRNA effectively ameliorates liver fibrosis in a mouse model.
- Targeting Col1α2 and the TGF-β/Smad pathway with sja-let-7 offers a potential therapeutic strategy for liver fibrosis.
