Comparative Effects of the Renin–Angiotensin System Blockers on Nonalcoholic Fatty Liver Disease and Insulin Resistance in C57Bl/6 Mice

Frantz, Eliete Dalla Corte; Penna-de-Carvalho, Aline; Batista, Thais de Medeiros; Águila, Márcia Barbosa; Mandarim-de-Lacerda, Carlos Alberto

doi:10.1089/met.2013.0129

Cited by 22 publications

(18 citation statements)

References 31 publications

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“…Additionally, this is related to the stimulation of lipogenic enzymes and the inhibition of mitochondrial β‐oxidation, thus contributing to the development of NAFLD (Frantz et al . ). These findings in the HFr group were lessened by exercise training, reverting hepatic steatosis, TAG accumulation and restoring the morphology of the hepatic parenchyma.…”

Section: Discussionmentioning

confidence: 97%

“…Some studies have revealed that RAS imbalance appears to promote hepatic disease, whereas activation of the ACE2/Ang(1–7)/Mas axis is able to prevent it (Frantz et al . ; Cao et al . ).…”

Section: Introductionmentioning

confidence: 99%

“…This ACE2/Ang(1-7)/Mas axis induces responses in opposition to the deleterious effects of ACE/Ang II/AT1R overactivity (Giani et al 2009;Cao et al 2014). Some studies have revealed that RAS imbalance appears to promote hepatic disease, whereas activation of the ACE2/Ang(1-7)/Mas axis is able to prevent it (Frantz et al 2014;Cao et al 2016).…”

Section: Introductionmentioning

confidence: 99%

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Exercise training modulates the hepatic renin–angiotensin system in fructose‐fed rats

Frantz

Medeiros

Giori

et al. 2017

Experimental Physiology

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What is the central question of this study? What are the effects of exercise training on the hepatic renin-angiotensin system and their contribution to damage resulting from fructose overload in rats? What is the main finding and its importance? Exercise training attenuated the deleterious actions of the angiotensin-converting enzyme/angiotensin II/angiotensin II type 1 receptor axis and increased expression of the counter-regulatory (angiotensin-converting enzyme 2/angiotensin (1-7)/Mas receptor) axis in the liver. Therefore, our study provides evidence that exercise training modulates the hepatic renin-angiotensin system, which contributes to reducing the progression of metabolic dysfunction and non-alcoholic fatty liver disease in fructose-fed rats. The renin-angiotensin system (RAS) has been implicated in the development of metabolic syndrome. We investigated whether the hepatic RAS is modulated by exercise training and whether this modulation improves the deleterious effects of fructose overload in rats. Male Wistar rats were divided into (n = 8 each) control (CT), exercise control (CT-Ex), high-fructose (HFr) and exercise high-fructose (HFr-Ex) groups. Fructose-drinking rats received d-fructose (100 g l ). After 2 weeks, CT-Ex and HFr-Ex rats were assigned to a treadmill training protocol at moderate intensity for 8 weeks (60 min day , 4 days per week). We assessed body mass, glucose and lipid metabolism, hepatic histopathology, angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2) activity, the angiotensin concentration and the expression profile of proteins affecting the hepatic RAS, gluconeogenesis and inflammation. Neither fructose overload nor exercise training influenced body mass gain and serum ACE and ACE2 activity. The HFr group showed hyperinsulinaemia, but exercise training normalized this parameter. Exercise training was effective in preventing hepatic steatosis and in preventing triacylglycerol and glycogen accumulation. Furthermore, exercise improved the response to the deleterious effects of HFr overload by normalizing the gluconeogenesis pathway and the protein levels of interleukin-6 and tumour necrosis factor-α. The HFr rats displayed increased hepatic ACE activity and protein expression and angiotensin II concentration, which were attenuated by exercise training. Exercise training restored the ACE2/angiotensin-(1-7)/Mas receptor axis. Exercise training may favour the counter-regulatory ACE2/angiotensin-(1-7)/Mas receptor axis over the classical RAS (ACE/angiotensin II/angiotensin II type 1 receptor axis), which could be responsible for the reduction of metabolic dysfunction and the prevention of non-alcoholic fatty liver disease.

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Section: Discussionmentioning

confidence: 97%

“…Some studies have revealed that RAS imbalance appears to promote hepatic disease, whereas activation of the ACE2/Ang(1–7)/Mas axis is able to prevent it (Frantz et al . ; Cao et al . ).…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Exercise training modulates the hepatic renin–angiotensin system in fructose‐fed rats

Frantz

Medeiros

Giori

et al. 2017

Experimental Physiology

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“…The consistency of body weight reductions in mice with genetic deficiencies of major renin angiotensin components contrasts with the phenotypes of pharmacological inhibition of these same proteins. A small number of studies using renin, ACE, or AT1 receptor inhibition have reported modest reductions in saturated fat diet induced body weight gain in mice, 38-44 while the vast majority of studies using pharmacological inhibition of renin, ACE, or AT1 receptors in mice fed a saturated fat diet have failed to observe any effect on body weight (more than 60 papers including 8,12,40,45-47 ). These data from mice is consistent with no data implicating body weight changes in humans treated with renin angiotensin system pharmacological inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Angiotensinogen Exerts Effects Independent of Angiotensin II

Lü

Howatt

et al. 2016

ATVB

138

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Objective This study determined whether angiotensinogen (AGT) has angiotensin (Ang)II-independent effects using multiple genetic and pharmacological manipulations. Approach and Results All study mice were in LDL receptor -/- background and fed a saturated fat-enriched diet. In mice with floxed alleles and a neomycin cassette in intron 2 of the AGT gene (hypoAGT mice), plasma AGT concentrations were > 90% lower compared to their wild type littermates. HypoAGT mice had lower SBP, less atherosclerosis, and diminished body weight gain and liver steatosis. Low plasma AGT concentrations and all phenotypes were recapitulated in mice with hepatocyte-specific deficiency of AGT or pharmacological inhibition of AGT by antisense oligonucleotide (ASO) administration. In contrast, inhibition of AGT cleavage by a renin inhibitor, aliskiren, failed to alter body weight gain and liver steatosis in LDL receptor -/- mice. In mice with established adiposity, administration of AGT ASO versus aliskiren led to equivalent reductions of SBP and atherosclerosis. AGT ASO administration ceased body weight gain and further reduced body weight, whereas aliskiren did not affect body weight gain during continuous saturated fat-enriched diet feeding. Structural comparisons of AGT proteins in zebrafish, mouse, rat and human revealed 4 highly conserved sequences within the des(AngI)AGT domain. des(AngI)AGT, through adeno-associated viral infection in hepatocyte-specific AGT deficient mice, increased body weight gain and liver steatosis, but did not affect atherosclerosis. Conclusions AGT contributes to body weight gain and liver steatosis through functions of the des(AngI)AGT domain, which are independent of AngII production.

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“…Therefore, the involvement of AGT II in NAFLD pathogenesis and in atherosclerotic plaque formation may provide one of the possible links between NAFLD and accelerated atherogenesis. Accordingly, the use of RAS blockers seems to be potentially useful as a therapeutic approach against NAFLD [12] and atherosclerosis [13]. To date, there is no single approved pharmacologic therapy to treat metabolic dysfunctions occurring in obesity, such as NAFLD and related atherosclerosis.…”

Section: Introductionmentioning

confidence: 99%

NAFLD and Atherosclerosis Are Prevented by a Natural Dietary Supplement Containing Curcumin, Silymarin, Guggul, Chlorogenic Acid and Inulin in Mice Fed a High-Fat Diet

et al. 2017

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Non-alcoholic fatty liver disease (NAFLD) confers an increased risk of cardiovascular diseases. NAFDL is associated with atherogenic dyslipidemia, inflammation and renin-angiotensin system (RAS) imbalance, which in turn lead to atherosclerotic lesions. In the present study, the impact of a natural dietary supplement (NDS) containing Curcuma longa, silymarin, guggul, chlorogenic acid and inulin on NAFLD and atherosclerosis was evaluated, and the mechanism of action was examined. C57BL/6 mice were fed an HFD for 16 weeks; half of the mice were simultaneously treated with a daily oral administration (os) of the NDS. NAFLD and atherogenic lesions in aorta and carotid artery (histological analysis), hepatic expression of genes involved in the NAFLD (PCR array), hepatic angiotensinogen (AGT) and AT1R mRNA expression (real-time PCR) and plasma angiotensin (ANG)-II levels (ELISA) were evaluated. In the NDS group, steatosis, aortic lesions or carotid artery thickening was not observed. PCR array showed upregulation of some genes involved in lipid metabolism and anti-inflammatory activity (Cpt2, Ifng) and downregulation of some genes involved in pro-inflammatory response and in free fatty acid up-take (Fabp5, Socs3). Hepatic AGT, AT1R mRNA and ANG II plasma levels were significantly lower with respect to the untreated-group. Furthermore, NDS inhibited the dyslipidemia observed in the untreated animals. Altogether, these results suggest that NDS prevents NAFLD and atherogenesis by modulating the expression of different genes involved in NAFLD and avoiding RAS imbalance.

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Comparative Effects of the Renin–Angiotensin System Blockers on Nonalcoholic Fatty Liver Disease and Insulin Resistance in C57Bl/6 Mice

Abstract: Enalapril was the most successful treatment in protecting against hepatic IR and NAFLD by enhancing hepatic insulin action, leptin, and gluconeogenesis and by reducing the lipogenic pathway and lipid accumulation in the liver.

Cited by 22 publications

References 31 publications

Exercise training modulates the hepatic renin–angiotensin system in fructose‐fed rats

Exercise training modulates the hepatic renin–angiotensin system in fructose‐fed rats

Angiotensinogen Exerts Effects Independent of Angiotensin II

NAFLD and Atherosclerosis Are Prevented by a Natural Dietary Supplement Containing Curcumin, Silymarin, Guggul, Chlorogenic Acid and Inulin in Mice Fed a High-Fat Diet

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