Resveratrol Relieves Hepatic Steatosis and Enhances the Effects of Atorvastatin in a Mouse Model of NAFLD by Regulating the Renin-Angiotensin System, Oxidative Stress, and Inflammation

Abstract

The classical renin-angiotensin system (RAS) axis is implicated in NAFLD development by promoting oxidative stress and inflammation, whereas the nonclassical axis antagonizes its effects. In the present study, we evaluated the effects of resveratrol (RSV), a polyphenol antioxidant, alone and in combination with atorvastatin (AT) on the RAS axes in NAFLD mice. Male C57/BL6 mice were fed a normal diet (control group) or a high-fat diet (HFD) for 12 weeks to induce NAFLD. Afterwards, the animals received AT (20 mg/kg), RSV (100 mg/kg/day), and AT + RSV (20 and 100 mg/kg/day) by oral gavage for 4 weeks. NAFLD animals exhibited swollen hepatocytes with numerous fat-containing vacuoles. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities were increased in NAFLD mice. Additionally, HFD mice exhibited dyslipidemia, as manifested by increased cholesterol (Chol), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C), and decreased high-density lipoprotein cholesterol (HDL-C). HFD significantly increased oxidative stress, as manifested by high levels of malondialdehyde and low paraoxonase 1 activity. Additionally, NAFLD mice showed significantly increased IL-1β, IL-6, and TNF-α expression and reduced IL-10 expression. An imbalance among RAS axes was evident as high expression levels of angiotensinogen, renin, and type 1 angiotensin receptor and reduced expression levels of angiotensin-converting enzyme 2 and angiotensin 1–7. RSV ameliorated these changes in NAFLD mice, which were comparable with the beneficial effects of AT. Interestingly, the ameliorative effects of AT increased considerably when it was administered in combination with RSV. Overall, our findings indicate that RSV attenuates HFD-induced NAFLD in mice, particularly when co-administered with AT, at least by regulating the RAS axes, oxidative stress, and inflammation.