Simvastatin improves microcirculatory function in nonalcoholic fatty liver disease through downregulation of oxidative and ale-rage stress.

Simvastatin improves microcirculatory function in nonalcoholic fatty liver disease through downregulation of oxidative and ale-rage stress.

• Autor
• Evelyn Nunes Goulart da Silva Pereira
• Co-autores
• Beatriz Peres Araujo , Karine Lino Rodrigues , Raquel Rangel Silvares , Carolina Souza Machado Martins , Edgar Eduardo Ilaquita Flores , Caroline Fernandes-Santos , Anissa Daliry
• Resumo

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  Non-alcoholic fatty liver disease (NAFLD) affects about 30% of the adult population and encompasses a broad spectrum of liver disease ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). Vascular dysfunction may play a fundamental role in the progression of NAFLD, as the extent of steatosis is associated with hepatic microcirculatory dysfunction, leading to tissue damage by increased oxidative stress and inflammation. Therefore, strategies targeting vascular homeostasis in NAFLD would be of great clinical importance. We investigated the mechanisms by which simvastatin (SV) exerts its protective effects on hepatic and adipose tissue microcirculation, assessing oxidative stress parameters, including the AGE-RAGE activation. NAFLD was established by a high-fat/high-carbohydrate diet (HFHC) for 13 weeks. SV was administered orally between weeks 6 and 13. Leukocyte recruitment was assessed by intravital microscopy, and microcirculation perfusion was assessed by Laser Speckle Contrast Imaging flowmetry. Results: HFHC exhibited metabolic changes indicative of NASH, whereas treatment with SV protected mice from developing NAFLD. SV prevented microcirculatory dysfunction in HFHC-fed mice, as evidenced by decreased numbers of rolling and adherent leukocytes in the hepatic and fat microcirculation, decreased activation of hepatic stellate cells (HSCs), and improved architecture and density of the hepatic capillary network. Additionally, SV restored hepatic and adipose tissue basal microvascular blood flow. Impairment of the endothelium-dependent vasodilatory response of adipose tissue to acetylcholine was restored by SV. Similarly, treatment with SV decreased lipid peroxidation in liver and adipose tissue and activation of the ALE-RAGE pathway. Our data suggest that SV improves microcirculatory function in NAFLD trough downregulation of oxidative and ALE-RAGE stress. Therefore, the microvascular and metabolic effects of SV may contribute to reposition statins for NAFLD treatment.

• Palavras-chave
• Nonalcoholic fatty liver disease, Simvastatin, Microcirculation, Liver, Adipose tissue
• Área Temática
• Vídeo-pôster / Sala 3 - Fisiologia Vascular

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