Published online Apr 27, 2019. doi: 10.4254/wjh.v11.i4.359
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
Obesity has been associated with hepatic overexpression of the renin-angiotensin system (RAS).
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.
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.
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.
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.
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.