Basic Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Apr 27, 2019; 11(4): 359-369
Published online Apr 27, 2019. doi: 10.4254/wjh.v11.i4.359
Beneficial effects of losartan or telmisartan on the local hepatic renin-angiotensin system to counter obesity in an experimental model
Francielle Graus-Nunes, Felipe de Oliveira Santos, Thatiany de Souza Marinho, Carolline Santos Miranda, Sandra Barbosa-da-Silva, Vanessa Souza-Mello
Francielle Graus-Nunes, Felipe de Oliveira Santos, Thatiany de Souza Marinho, Carolline Santos Miranda, Sandra Barbosa-da-Silva, Vanessa Souza-Mello, Laboratório de Morfometria, Metabolismo e Doenças Cardiovasculares, Departamento de Anatomia, Instituto de Biologia Roberto Alcântara Gomes, Rio de Janeiro 20551-030, Brazil
Author contributions: Graus-Nunes F performed the majority of experiments and analyzed the data; Santos FO, Marinho TS and Miranda CS performed the molecular investigations; Graus-Nunes F, Oliveira FO, Marinho TS and Miranda CS participated equally in the handling of animals; Graus-Nunes F, Barbosa-da-Silva S and Souza-Mello V designed and coordinated the research; Graus-Nunes F, Oliveira FO and Souza-Mello V wrote the paper.
Supported by: Fundação Carlos Chagas Filho de Apoio àPesquisa do Estado do Rio de Janeiro, No. E-26/202.888/2015 for V.S-M.
Institutional review board statement: The study protocol is in line with the National Institute of Health (NIH, publication number 85–23, revised in 1996) and was approved by the Institutional Review (scientific) Board (IBRAG IRB-013/15) of the Institute of Biology Roberto Alcântara Gomes (IBRAG), State University of Rio de Janeiro.
Institutional animal care and use committee statement: The study was approved by the local animal care and use committee, protocol CEUA/013/2015.
Conflict-of-interest statement: None of the authors have a conflict of interest to report.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Vanessa Souza-Mello, Adjunct professor, Laboratório de Morfometria, Metabolismo e Doenças Cardiovasculares, Departamento de Anatomia, Instituto de Biologia Roberto Alcântara Gomes, Av. 28 de setembro 87 fundos, Rio de Janeiro 20551-030, Brazil. souzamello.uerj@gmail.com
Telephone: +55-21-28688689 Fax: +55-21-2868-8033
Received: December 11, 2018
Peer-review started: December 11, 2018
First decision: January 27, 2019
Revised: February 23, 2019
Accepted: March 16, 2019
Article in press: March 16, 2019
Published online: April 27, 2019
Processing time: 136 Days and 3.6 Hours
Abstract
BACKGROUND

Obesity has been associated with hepatic overexpression of the renin-angiotensin system (RAS).

AIM

To evaluate the action of two angiotensin II (ANGII) receptor blockers (losartan or telmisartan) on the modulation of local hepatic RAS and the resulting metabolic effects in a diet-induced obesity murine model.

METHODS

Twenty C57BL/6 mice were randomly divided into two nutritional groups for 10 wk: control group (C, n = 5, 10% of energy as fat) or high-fat group (HF, n = 15, 50% of energy as fat). After treatment started, the HF group was randomly divided into three groups: untreated HF group (n = 5), HF treated with losartan (HFL, n = 5) and HF treated with telmisartan (HFT, n = 5). The treatments lasted for 5 wk, and the dose was 10 mg/kg body mass.

RESULTS

HF diet induced body mass gain (+28%, P < 0.0001), insulin resistance (+69%, P = 0.0079), high hepatic triacylglycerol (+127%, P = 0.0004), and overexpression of intrahepatic angiotensin-converting enzyme (ACE) 1/ ANGII type 1 receptor (AT1r) (+569.02% and +141.40%, respectively, P < 0.0001). The HFL and HFT groups showed higher ACE2/rMAS gene expression compared to the HF group (ACE2: +465.57%, P = 0.0002 for HFL and +345.17%, P = 0.0049 for HFT; rMAS: +711.39%, P < 0.0001 for HFL and +539.75%, P < 0.0001 for HFT), followed by reduced insulin/glucose ratio (-30% for HFL and -33% for HFT, P = 0.0181), hepatic triacylglycerol levels (-28%, P = 0.0381 for HFL; and -45%, P = 0.0010 for HFT, and Plin2 expression.

CONCLUSION

Modulation of the intrahepatic RAS, with favored involvement of the ACE2/rMAS axis over the ACE1/AT1r axis after losartan or telmisartan treatments, caused hepatic and metabolic beneficial effects as demonstrated by reduced hepatic triacylglycerol levels coupled with reduced PLIN 2 expression and improved glycemic control.

Keywords: Liver, Telmisartan, Losartan, Obesity, Angiotensin II type 1 receptor, C57BL/6 mouse

Core tip: Studies that address regulation of the local renin-angiotensin system (RAS) have accumulated since it was established that obese subjects overexpress components of the classical RAS in organs like the liver. Herein, we show evidence that two different angiotensin II receptor blockers modulate the intrahepatic RAS, favoring the angiotensin-converting enzyme (ACE) 2/rMAS axis over the ACE1/angiotensin II type 1 receptor in mice fed a high-fat diet. These drugs mitigated hepatic steatosis by reducing hepatic triacylglycerol levels and decreasing body mass and improving glycemic control. These drugs could be a viable option to treat non-alcoholic fatty liver disease in obese and/or hypertensive patients.