ACE inhibition and AT1 receptor blockade prevent fatty liver and fibrosis in obese zucker rats

Abstract

Objective:Non-alcoholic steatohepatitis (NASH), which is a common liver disease in industrialized countries, is associated with obesity, hypertension, and type-2 diabetes (metabolic syndrome). Since angiotensin II (ANG II) has been suggested to play an important role in liver inflammation and fibrosis, the purpose of this study was to investigate whether therapy against renin-angiotensin system (RAS) may provide some beneficial effect in liver of an animal model of metabolic syndrome.Methods and Procedures:For 6 months, obese Zucker rats (OZRs) were treated as follows: OZR-group, OZR Perindopril (P) group, OZR Irbesartan (IRB) group, OZR Amlodipine (AML) group, and lean Zucker rats (LZRs) group as a control. Livers were evaluated by immunohistochemistry techniques using corresponding antibodies.Results:All treated groups showed a similar reduction in blood pressure compared to untreated OZR. Therapy either with IRB or P improves insulin sensitivity and reduces hepatic enzyme level with respect to untreated OZR. Conversely, AML failed to modify both parameters. Untreated OZR displayed higher hepatic ANG II levels and steatosis together with a marked increase in tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and transforming growth factor-Β"1 (TGF-Β"1) level compared to LZR. Following RAS inhibition either by P or IRB, a significant reduction (P < 0.01) in the immunostaining of TNF-α, IL-6 and TGF-Β"1 compared to untreated OZR was observed.Discussion:These results indicate that ANG II expression is increased in the liver of these animals with steatohepatitis. Furthermore, RAS control by either angiotensin-converting enzyme inhibition or AT1 receptor blockade seems to provide a beneficial modulation concerning the inflammatory response to liver injury in this model. Consequently, blockade of RAS could be a new approach to prevent or to treat patients with NASH. © 2008 The Obesity Society.