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.
Highlights
The renin-angiotensin system (RAS) is critical in the regulation of glycolipid metabolism and insulin sensitivity, which are closely related to metabolic syndromes [e.g., obesity, type 2 diabetes mellitus (T2DM), and non-alcoholic fatty liver disease (NAFLD)] (Marcus et al, 2013)
We found that angiotensin-converting enzyme (ACE) and AT1R gene expression was markedly higher in the liver, and the ACE2 and its Mas receptor gene expression was slightly higher in the mice that were fed a high-fat-diet induced NAFLD model group (HFD) for 16 weeks, compared to the standard diet control group (SD)-fed mice. (Figures 1A–D)
Compared to the SD-fed mice, ACE protein expression was markedly higher in livers of the mice fed a HFD for 16 weeks, which was consistent with the corresponding gene expression, whereas the ACE2 protein content was decreased in NAFLD mice (Figures 1E, F)
Summary
The renin-angiotensin system (RAS) is critical in the regulation of glycolipid metabolism and insulin sensitivity, which are closely related to metabolic syndromes [e.g., obesity, type 2 diabetes mellitus (T2DM), and non-alcoholic fatty liver disease (NAFLD)] (Marcus et al, 2013). The two RAS axes identified both in circulation and locally in the liver are dramatically up-regulated in animal models of chronic liver diseases and in patients with chronic hepatitis and hepatic fibrosis (Lubel et al, 2009; Zhang W. et al, 2013). This indicates that liver injury induces excessive RAS activation; the precise role of the hepatic RAS in NAFLD remains poorly understood. The factors regulating the expression and activity of the RAS are largely unknown, and large research gaps remain
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