Oral Formulation of Angiotensin-(1–7) Improves Lipid Metabolism and Prevents High-Fat Diet–Induced Hepatic Steatosis and Inflammation in Mice

Abstract

Abstract-Angiotensin (Ang)-(1-7) has been described as an important tool on treating and preventing metabolic disorders. In this study, we aimed to evaluate the effect of an oral formulation of Ang-(1-7) included in hydroxypropylβ-cyclodextrin (HPβCD/Ang- [1][2][3][4][5][6][7]) on hepatic function, steatosis, and on liver inflammatory markers expression in mice treated with a high-fat diet. Male FVB/N mice were divided into 4 groups and fed for 60 days, with each group receiving 1 of the following diets: standard diet+HPβCD, standard diet+Ang-(1-7)/HPβCD, high-fat diet+HPβCD, or highfat diet+Ang-[1-7]/HPβCD. Body weight, food intake, and blood parameters, such as total cholesterol, triglyceride, alaninetransaminases, and aspartate transaminases, were evaluated. Immunohistochemical analyses were performed for inflammatory markers tumor necrosis factor-α and interleukin-6. Expression of angiotensin converting enzyme, angiotensin-converting enzyme-2, interleukin-1β, tumor necrosis factor-α, interleukin-6, transforming growth factor-β, acetyl-CoA carboxylase, carbohydrate-responsive element-binding protein, peroxisome proliferator-activated receptor-γ, and sterol regulatory element-binding proteins-1c was evaluated by quantitative real-time polymerase chain reaction. The major findings of our study included reduced liver fat mass and weight, decreased plasma total cholesterol, triglyceride, and alaninetransaminase enzyme levels in the oral Ang-(1-7)-treated groups compared with the control groups. These results were accompanied by a significant reduction in tumor necrosis factor-α and interleukin-6 mRNA expression in the liver. Analyses of liver adipogenesis-related genes by quantitative real-time polymerase chain reaction showed that acetyl-CoA carboxylase, peroxisome proliferator-activated receptor-γ, and sterol regulatory element-binding proteins1c mRNA expression were significantly suppressed. In conclusion, we observed that treatment with Ang-(1-7) improved metabolism and decreased proinflammatory profile and fat deposition in liver of mice. The renin-angiotensin system (RAS) is now recognized to play an important role in the development of cardiovascular and metabolic disorders. [10][11][12][13] The RAS consists primarily of an enzymatic cascade in which angiotensinogen is converted to angiotensin (Ang) I and subsequently to Ang II by the actions of renin and Ang-converting enzyme (ACE), respectively. 14 Ang-(1-7) is formed mainly from Ang II by ACE-2 and indirectly from Ang I.14 The ACE-2/Ang-(1-7)/Mas axis has been suggested as an important counter-regulatory arm in the RAS with effects opposing those of ACE/Ang II/Ang II receptor, type 1. 13Recent studies showed an important participation of RAS in the nonalcoholic fatty liver disease (NAFLD) development and progression. The Ang II has been implicated as a major player in the altered hepatic lipid metabolism observed in NAFLD. Genetic disruption of several RAS components in rodent models results in a protection from high-fat diet (HFD)-induced obesity. [15...

Heat Shock Prevents Insulin Resistance–Induced Vascular Complications by Augmenting Angiotensin-(1-7) Signaling

“…Like ACE inhibitors or AT 1 receptor blockers, ANG-(1-7) attenuates the characteristics of metabolic syndrome (49). Oral formulation of ANG-(1-7) improves metabolism, and decreases the proinflammatory profile and fat deposition in HFD-fed mice as well as hypertensive rats (50,51). Prolonged ANG-(1-7) treatment has also been shown to improve endothelial dysfunction and oxidative stress in a mouse model of obesity (52).…”

Mas and Its Related G Protein–Coupled Receptors, Mrgprs

“…The absence of the antidiuretic action of Ang-(1-7) in Mas-KO mice is in agreement with the antidiuretic effect of Ang-(1-7) in water-loaded rats (Santos and Baracho, 1992). Diverging from many reports describing Mas-mediated anti-inflammatory effects in different tissues (Al-Maghrebi et al, 2009;da Silveira et al, 2010;El-Hashim et al, 2012;Giani et al, 2012;Jiang et al, 2012;Santos et al, 2012;Souza and Costa-Neto, 2012;Sukumaran et al, 2012;Chen et al, 2013;Feltenberger et al, 2013;Moore et al, 2013;Regenhardt et al, 2013;Wagenaar et al, 2013;Wang et al, 2013c;Acuna et al, 2014;Meng et al, 2014), in the kidney, a proinflammatory role for Ang-(1-7) and Mas was reported by using a model of unilateral ureteral obstruction in mice (Esteban et al, 2009). In contrast, anti-inflammatory and beneficial effects of Ang-(1-7) were observed in other models of kidney injury (Singh et al, 2010b;Moon et al, 2011;Bernardi et al, 2012;Giani et al, 2012;Harris, 2012;Chou et al, 2013;Santos et al, 2013b;Zhang et al, 2014).…”

Emerging Liver–Kidney Interactions in Nonalcoholic Fatty Liver Disease

“…ACE2-Ang(1-7) axis expression has been found to be downregulated in obesity [11], and hepatic and experimental renal ACE2-Ang(1-7) deficiency enhanced high-fat diet-induced NASH, adipose tissue inflammation, and CKD [12], whereas Ang(1-7) analogs or ACE2 activators diminazene and xanthenone reversed these changes and ameliorated adipose tissue dysfunction, vascular inflammation, and liver and kidney disease [13][14][15][16][17]. Therefore, approaches expression, depending on the methylation sites.…”