Liraglutide Attenuates Non-Alcoholic Fatty Liver Disease in Mice by Regulating the Local Renin-Angiotensin System

Abstract

The renin-angiotensin system (RAS) is involved in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and represents a potential therapeutic target for NAFLD. Glucagonlike peptide-1 (GLP-1) signaling has been shown to regulate the RAS within various local tissues. In this study, we aimed to investigate the functional relationship between GLP-1 and the local RAS in the liver during NAFLD. Wild-type and ACE2 knockout mice were used to establish a high-fat-induced NAFLD model. After the mice were treated with liraglutide (a GLP-1 analogue) for 4 weeks, the key RAS component genes were upregulated in the liver of NAFLD mice. Liraglutide treatment regulated the RAS balance, preventing a reduction in fatty acid oxidation gene expression and increasing gluconeogenesis and the expression of inflammation-related genes caused by NAFLD, which were impaired in ACE2 knockout mice. Liraglutide-treated HepG2 cells exhibited activation of the ACE2/Ang1-7/Mas axis, increased fatty acid oxidation gene expression, and decreased inflammation, which could be reversed by A779 and AngII. These results indicate that the local RAS in the liver becomes overactivated in response to NAFLD. Moreover, ACE2 knockout increases the severity of liver steatosis. Liraglutide has a negative and antagonistic effect on the ACE/AngII/AT1R axis, a positive impact on the ACE2/Ang1-7/Mas axis, and is mediated through the PI3K/AKT pathway. This may represent a potential new mechanism by which liraglutide improves NAFLD.

A comprehensive guide to the pharmacologic regulation of angiotensin converting enzyme 2 (ACE2), the SARS-CoV-2 entry receptor

“…In another study, liraglutide increased pulmonary ACE2 expression in rats with in utero growth retardation ( Fandino et al, 2018 ). Similarly, liraglutide completely reversed reduced hepatic ACE2 mRNA expression in mice with high-fat-induced liver disease through activation of the phosphatidylinositol-3-kinase (PI3K/Akt) signaling pathway in HepG2 cells ( M. Yang et al, 2020 ). Liraglutide and another antidiabetic, linagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, improved Ang-II-induced cardiovascular pathology, counteracted Ang-II-induced downregulation of Smad7, reduced collagen synthesis and cardiac fibrosis, and upregulated myocardial expression and activity of ACE2 ( L. H. Zhang et al, 2015 ).…”

Incretin Hormones in Obesity and Related Cardiometabolic Disorders: The Clinical Perspective

“…Moreover, incretin mimetics have been shown to directly reduce hepatocyte steatosis by modulating elements of the insulin signaling pathway [ 233 ]. The treatment with liraglutide in animal models has been recently associated with the improvement in hepatic steatosis by downregulation of the expression of inflammatory signaling mediators [ 234 ] and by regulating the local renin–angiotensin system [ 235 ].…”

Treatment of Fatty Liver Disease: The Present and the Future

“…Liraglutide was also found to downregulate ACE activity. This led to the suppression of gluconeogenesis and inflammation in the liver thereby preventing NAFLD progression [ 31 ].…”