Liraglutide Attenuates Non-Alcoholic Fatty Liver Disease in Mice by Regulating the Local Renin-Angiotensin System
Open Access
- 8 April 2020
- journal article
- research article
- Published by Frontiers Media SA in Frontiers in Pharmacology
- Vol. 11, 432
- https://doi.org/10.3389/fphar.2020.00432
Abstract
The renin-angiotensin system (RAS) system is involved in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), which represents a potential therapeutic target for NAFLD. The glucagon-like 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 four weeks, the key RAS component genes were up-regulated in the liver of NAFLD mice. Liraglutide treatment can regulate the RAS system balance, preventing a reduction in fatty acid oxidation gene expression, increase in gluconeogenesis, and expression of inflammation-related genes caused by NAFLD, which is impaired in ACE2KO 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 seriousness of liver steatosis. Liraglutide has a negative and antagonistic effect on the ACE/AngII/AT1R axis, 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.Keywords
Funding Information
- National Natural Science Foundation of China (81570700, 81974104)
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