• Wei Wang, Caiyan Zhao, Junying Zhou, Zhen Zhen, Yadong Wang, and Chuan Shen.
• Department of Infectious Diseases, the Third Affiliated Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China.
• Plos One. 2013 Jan 1; 8 (10): e76538.

BackgroundSimvastatin 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.MethodsA 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.ResultsWith 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.ConclusionsSimvastatin 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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