Simvastatin Ameliorates Liver Fibrosis via Mediating Nitric Oxide Synthase in Rats with Non-Alcoholic Steatohepatitis-Related Liver Fibrosis

Abstract

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 24th 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.

Beneficial effects of diacerein on adipokines and pro-inflammatory cytokines involved in diet-induced nonalcoholic steatohepatitis in rats

“…These findings are in accordance with previous researches. 6,7 The results of the present study also showed significant increase in serum levels of blood lipids, TNF-α, IL-1β, IL-6, leptin and visfatin with increased insulin resistance index (HOMA-IR) and decreased adiponectin level in NASH rats, thus confirming the role of the above factors on the pathogenesis of NASH.…”

“…Several studies found that high-fat and high-cholesterol diet induce liver steatosis, steatohepatitis, fibrosis, necrosis and cause excess oxidative stress in the liver. 6,7 Besides, dyslipidaemia, insulin resistance, obesity and elevated serum aminotransferases accompany these liver changes.…”

Histological Effects of Aqueous Extract of Moringa oleifera on the Liver Tissues of Wistar rats fed with High Fat Diet

“…Macrovesicular steatosis are more abundant than the microvesicular as was observed above. The findings is in consonant with that of human and animal forms of non-alcoholic fatty liver disease NAFLD which is characterized by a mixed macro and microvesicular type of hepatic steatosis [22][23][24][25][26][27][28] .The histology of the liver tissue of rats fed with high fat diet exhibited significant alteration in the architecture of the liver tissue. The alteration include micro and macro vascular steatosis, increased fatty infiltration, inflammation , sinusoidal dilation, degeneration of veins and vacuolization as compared to normal liver histology in figure A,C.…”

The role of iNOS in cholesterol-induced liver fibrosis

“…1,2 Fibrosis associated with NASH has been suggested to be the physiological consequence of chronic hepatic injury, necrosis, and inflammation as well as unbalanced intrahepatic lipid metabolism (steatosis), insulin resistance, oxidative stress, and lipid peroxidation. [3][4][5] Different lipid molecules may mediate the pathogenesis and the progression of NASH. To date, the identity of a dominant lipid molecule/s, which causes liver lipotoxicity, is still unknown.…”