Dataset Information

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. 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 4 weeks, the key RAS component genes were up-regulated 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.

SUBMITTER: Yang M

PROVIDER: S-EPMC7156971 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Yang Mengying M Ma Xiaoyi X Xuan Xiuping X Deng Hongjun H Chen Qi Q Yuan Li L

Frontiers in pharmacology 20200408

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. 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 ...[more]

PMID: 32322207

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Project description:Background: The prevalence of non-alcoholic fatty liver disease (NAFLD) keeps growing recently. Purpose: To investigate the effects and mechanisms of naringenin (NAR) on NAFLD. Methods: High-fat diet (HFD)-induced NAFLD rats were orally administered with NAR at 10, 30, and 90 mg/kg for 2 weeks. The serum level of triglyceride (TG), total cholesterol (TC), glutamic-oxaloacetic transaminase (AST), and glutamic-pyruvic transaminase (ALT) was measured. The hepatic histology was detected by H&E and oil red O staining. L02 and Huh-7 cells were induced by sodium oleate to establish a NAFLD cell model. The effects of NAR on lipid accumulation were detected by oil red O staining. The glucose uptake and ATP content of 3T3-L1 adipocytes and C2C12 myotubes were measured. The expression of proteins of the AMPK signaling pathway in 3T3-L1 adipocytes and C2C12 myotubes was assessed by Western blotting. The mitochondrial biogenesis of 3T3-L1 adipocytes and C2C12 myotubes was measured by mitotracker orange staining and Western blotting. The biomarkers of autophagy were detected by Western blotting and immunofluorescence. The binding of NAR to AMPKγ1 was analyzed by molecular docking. Chloroquine and compound C were employed to block autophagic flux and AMPK, respectively. Results: NAR alleviated HFD-induced NAFLD in rats at 10, 30, and 90 mg/kg. NAR attenuated lipid accumulation in L02 and Huh-7 cells at 0.7, 2.2, 6.7, and 20 μM. NAR increased glucose uptake, decreased the ATP content, activated the CaMKKβ/AMPK/ACC pathway, and enhanced the mitochondrial biogenesis in 3T3-L1 adipocytes and C2C12 myotubes. NAR increased autophagy and promoted the initiation of autophagic flux in 3T3-L1 preadipocytes and C2C12 myoblasts, while it inhibited autophagy in NAFLD rats, 3T3-L1 adipocytes, and C2C12 myotubes. Molecular docking showed that NAR binds to AMPKγ1. Compound C blocked effects of NAR on lipid accumulation and autophagy in L02 cells. Conclusion: NAR alleviates NAFLD by increasing energy expenditure and regulating autophagy via activating AMPK directly and indirectly. The direct binding of NAR and AMPKγ1 needs further validation.

Dataset Information

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

Publications

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

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