Simvastatin Improves Microcirculatory Function in Nonalcoholic Fatty Liver Disease and Downregulates Oxidative and ALE-RAGE Stress

• Published in: Nutrients Vol. 14; no. 3; p. 716
• Main Authors: Pereira, Evelyn Nunes Goulart da Silva, Araujo, Beatriz Peres de, Rodrigues, Karine Lino, Silvares, Raquel Rangel, Martins, Carolina Souza Machado, Flores, Edgar Eduardo Ilaquita, Fernandes-Santos, Caroline, Daliry, Anissa
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 08-02-2022; MDPI
• Subjects: Adipose tissue; Advanced glycosylation end products; Animals; Antioxidants; Automation; Blood flow; Carbohydrates; Cell activation; Cholesterol; Computer architecture; Diet; Endothelium; Enzymatic activity; Enzyme activity; Fatty liver; Fibrosis; Glucose; Glycosylation; Hepatitis; High carbohydrate diet; High fat diet; Inflammation; Lipid peroxidation; Lipids; Liver; Liver diseases; Metabolism; Metabolites; Mice; Microcirculation; Microvasculature; Non-alcoholic Fatty Liver Disease - etiology; nonalcoholic fatty liver disease; Oxidative stress; Oxidative Stress - physiology; Peroxidation; Simvastatin; Simvastatin - pharmacology; Simvastatin - therapeutic use; Steatosis; United States > US; Argentina; adipose tissue; simvastatin; nonalcoholic fatty liver disease; liver; microcirculation
• ISSN: 2072-6643; 2072-6643
• DOI: 10.3390/nu14030716

Increased reactive oxidative stress, lipid peroxidation, inflammation, and fibrosis, which contribute to tissue damage and development and progression of nonalcoholic liver disease (NAFLD), play important roles in microcirculatory disorders. We investigated the effect of the modulatory properties of simvastatin (SV) on the liver and adipose tissue microcirculation as well as metabolic and oxidative stress parameters, including the advanced lipoxidation end product-receptors of advanced glycation end products (ALE-RAGE) pathway. SV was administered to an NAFLD model constructed using a high-fat-high-carbohydrate diet (HFHC). HFHC caused metabolic changes indicative of nonalcoholic steatohepatitis; treatment with SV protected the mice from developing NAFLD. SV prevented microcirculatory dysfunction in HFHC-fed mice, as evidenced by decreased leukocyte recruitment to hepatic and fat microcirculation, decreased hepatic stellate cell activation, and improved hepatic capillary network architecture and density. SV restored basal microvascular blood flow in the liver and adipose tissue and restored the endothelium-dependent vasodilatory response of adipose tissue to acetylcholine. SV treatment restored antioxidant enzyme activity and decreased lipid peroxidation, ALE-RAGE pathway activation, steatosis, fibrosis, and inflammatory parameters. Thus, SV may improve microcirculatory function in NAFLD by downregulating oxidative and ALE-RAGE stress and improving steatosis, fibrosis, and inflammatory parameters.