Simvastatin Reduces Hepatic Oxidative Stress and Endoplasmic Reticulum Stress in Nonalcoholic Steatohepatitis Experimental Model

Abstract

Objective. In this study, we evaluated the efficacy of simvastatin in the treatment of nonalcoholic steatohepatitis induced by methionine and choline-deficient diet in mice and its possible effect on factors involved in the pathogenesis of the disease including oxidative stress and endoplasmic reticulum stress. Method. Male C57BL6 mice were fed either a normal diet (control) or a methionine and choline-deficient diet for four weeks and then treated orally with simvastatin (4 mg/kg once a day) for two final weeks. At the end of the experimental period, liver integrity, biochemical analysis, hepatic lipids, histology, DNA damage, biomarkers of oxidative stress, and endoplasmic reticulum stress were assessed. Results. Simvastatin treatment was able to significantly reduce hepatic damage enzymes and hepatic lipids and lower the degree of hepatocellular ballooning, without showing genotoxic effects. Simvastatin caused significant decreases in lipid peroxidation, with some changes in antioxidant enzymes superoxide dismutase and glutathione peroxidase. Simvastatin activates antioxidant enzymes via Nrf2 and inhibits endoplasmic reticulum stress in the liver. Conclusions. In summary, the results provide evidence that in mice with experimental nonalcoholic steatohepatitis induced by a methionine and choline-deficient diet, the reduction of liver damage by simvastatin is associated with attenuated oxidative and endoplasmic reticulum stress.

Atorvastatin Modulates Bile Acid Homeostasis in Mice with Diet-Induced Nonalcoholic Steatohepatitis

“…Indeed, data from large prospective randomized clinical trials suggest that atorvastatin especially ameliorates NAFLD/NASH and reduces CVS events by two fold relative to those with normal liver function [ 8 ]. Consistent with these findings, several animal studies have shown that statins attenuate NAFLD and decrease liver inflammation, steatosis, and fibrosis [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. Molecular studies have suggested that the mechanisms of statins’ protective activity in NASH include the activation of the adenosine monophosphate–activated protein kinase α (AMPKα) and the inhibition of c-Jun N-terminal kinases (JNK1/2), Rho kinase [ 18 ], and liver X receptor α–related genes [ 19 ].…”

Empagliflozin Attenuates Non-Alcoholic Fatty Liver Disease (NAFLD) in High Fat Diet Fed ApoE(-/-) Mice by Activating Autophagy and Reducing ER Stress and Apoptosis

“…Notably, the present study further expanded on the mechanisms underlying such empagliflozin-induced beneficial effects on NAFLD/NASH, focusing on the gene and protein hepatic expression of factors involved in ER stress, autophagy and apoptosis which are crucial processes implicated in NAFLD development and progression [ 35 , 36 , 37 , 38 , 39 ]. Indeed, it is now well-established that under normal (unstressed) conditions, IRE1, PERK and ATF6 are inactivated upon binding to GRP78/BiP, whereas under stress conditions GRP-78/BiP dissociates from the ER stress sensors, thus activating the three arms of the UPR [ 37 ].…”

Implications on the Therapeutic Potential of Statins via Modulation of Autophagy

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