Simvastatin ameliorates liver fibrosis via mediating nitric oxide synthase in rats with non-alcoholic steatohepatitis-related liver fibrosis.
BACKGROUND: Simvastatin exerts pleiotropic effects on cardiovascular system. However, its effect on non-alcoholic fatty liver disease, especially the liver fibrosis, remains obscure. We aimed to clarify the relationship between simvastatin and liver fibrosis both in vivo and in vitro. METHODS: A Hig...
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| Format: | Article |
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Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3788732?pdf=render |
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| author | Wei Wang Caiyan Zhao Junying Zhou Zhen Zhen Yadong Wang Chuan Shen |
| author_facet | Wei Wang Caiyan Zhao Junying Zhou Zhen Zhen Yadong Wang Chuan Shen |
| author_sort | Wei Wang |
| collection | DOAJ |
| description | BACKGROUND: Simvastatin exerts pleiotropic effects on cardiovascular system. However, its effect on non-alcoholic fatty liver disease, especially the liver fibrosis, remains obscure. We aimed to clarify the relationship between simvastatin and liver fibrosis both in vivo and in vitro. METHODS: A High-fat diet was given to establish rat models with non-alcoholic steatohepatitis (NASH)-related liver fibrosis and simvastatin (4mg·kg(-1)·d(-1)) was administrated intragastrically until hepatic histological findings confirmed the appearance of fibrosis. Human hepatic stellate cell (HSC) line lx-2 cells were cultured in an adipogenic differentiating mixture (ADM) and then were treated with transforming growth factorβ1 (TGF-β1), served as a positive control, simvastatin, TGF-β1 plus simvastatin, Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME, a inhibitor of nitric oxide synthase), and L-NAME plus simvastatin, respectively. The expressions of endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), and Collagen І as well as cellular α-smooth muscle actin (α-SMA) were measured by real-time reverse transcriptase-polymerase chain reaction (qRT-PCR) and Western blot in liver tissue and HSC. RESULTS: With the progress of NASH-related fibrosis, hepatic mRNA and protein expressions of iNOS, α-SMA, and Collagen І were increased while those of eNOS were decreased. Compared with model rats in 24(th) week group, rats in simvastatin group had less expressions of iNOS, α-SMA, and Collagen І and more expressions of eNOS. In vitro, LX-2 cells acquired quiescent phenotype when cultured in ADM, and TGF-β1 could activate the quiescent HSC. Simvastatin inhibited LX-2 cells activation due to TGF-β1 or L-NAME by increasing the expression of eNOS and decreasing the expression of iNOS. CONCLUSIONS: Simvastatin improves the prognosis of NASH-related fibrosis by increasing the expression of eNOS, decreasing the expression of iNOS, and inhibiting the activation of HSC. |
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| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-13T02:17:22Z |
| publishDate | 2013-01-01 |
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| spelling | doaj.art-cb3bb0fa33d94923884e171a3829b5b02022-12-22T00:02:51ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-01810e7653810.1371/journal.pone.0076538Simvastatin ameliorates liver fibrosis via mediating nitric oxide synthase in rats with non-alcoholic steatohepatitis-related liver fibrosis.Wei WangCaiyan ZhaoJunying ZhouZhen ZhenYadong WangChuan ShenBACKGROUND: Simvastatin exerts pleiotropic effects on cardiovascular system. However, its effect on non-alcoholic fatty liver disease, especially the liver fibrosis, remains obscure. We aimed to clarify the relationship between simvastatin and liver fibrosis both in vivo and in vitro. METHODS: A High-fat diet was given to establish rat models with non-alcoholic steatohepatitis (NASH)-related liver fibrosis and simvastatin (4mg·kg(-1)·d(-1)) was administrated intragastrically until hepatic histological findings confirmed the appearance of fibrosis. Human hepatic stellate cell (HSC) line lx-2 cells were cultured in an adipogenic differentiating mixture (ADM) and then were treated with transforming growth factorβ1 (TGF-β1), served as a positive control, simvastatin, TGF-β1 plus simvastatin, Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME, a inhibitor of nitric oxide synthase), and L-NAME plus simvastatin, respectively. The expressions of endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), and Collagen І as well as cellular α-smooth muscle actin (α-SMA) were measured by real-time reverse transcriptase-polymerase chain reaction (qRT-PCR) and Western blot in liver tissue and HSC. RESULTS: With the progress of NASH-related fibrosis, hepatic mRNA and protein expressions of iNOS, α-SMA, and Collagen І were increased while those of eNOS were decreased. Compared with model rats in 24(th) week group, rats in simvastatin group had less expressions of iNOS, α-SMA, and Collagen І and more expressions of eNOS. In vitro, LX-2 cells acquired quiescent phenotype when cultured in ADM, and TGF-β1 could activate the quiescent HSC. Simvastatin inhibited LX-2 cells activation due to TGF-β1 or L-NAME by increasing the expression of eNOS and decreasing the expression of iNOS. CONCLUSIONS: Simvastatin improves the prognosis of NASH-related fibrosis by increasing the expression of eNOS, decreasing the expression of iNOS, and inhibiting the activation of HSC.http://europepmc.org/articles/PMC3788732?pdf=render |
| spellingShingle | Wei Wang Caiyan Zhao Junying Zhou Zhen Zhen Yadong Wang Chuan Shen Simvastatin ameliorates liver fibrosis via mediating nitric oxide synthase in rats with non-alcoholic steatohepatitis-related liver fibrosis. PLoS ONE |
| title | Simvastatin ameliorates liver fibrosis via mediating nitric oxide synthase in rats with non-alcoholic steatohepatitis-related liver fibrosis. |
| title_full | Simvastatin ameliorates liver fibrosis via mediating nitric oxide synthase in rats with non-alcoholic steatohepatitis-related liver fibrosis. |
| title_fullStr | Simvastatin ameliorates liver fibrosis via mediating nitric oxide synthase in rats with non-alcoholic steatohepatitis-related liver fibrosis. |
| title_full_unstemmed | Simvastatin ameliorates liver fibrosis via mediating nitric oxide synthase in rats with non-alcoholic steatohepatitis-related liver fibrosis. |
| title_short | Simvastatin ameliorates liver fibrosis via mediating nitric oxide synthase in rats with non-alcoholic steatohepatitis-related liver fibrosis. |
| title_sort | simvastatin ameliorates liver fibrosis via mediating nitric oxide synthase in rats with non alcoholic steatohepatitis related liver fibrosis |
| url | http://europepmc.org/articles/PMC3788732?pdf=render |
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