Abstract 464: Non-alcoholic Fatty Liver Disease Produced by Mas Deficiency in ApoE-KO Mice
The non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and recent studies have shown the involvement of the renin-angiotensin system in this pathology. We have previously shown that Mas deficiency in ApoE-KO mice results in a marked increase in hepatic triglyceride and total lipids. However, the role of the Ang-(1-7)/Mas in the NAFLD is still not fully understood. The aim of this study was to evaluate the role of Mas in liver steatosis using a double knockout Mas/ApoE (DKO) mice. C57Bl6, Mas-/- (Mas), ApoE-/- (ApoE), and DKO mice were killed at 20 weeks of age. Mas deficiency in ApoE leads to reduced insulin sensitivity and serum leptin (WT = 2.27 ± 0.73 ng/mL, n =5; Mas = 0.96 ± 0.25 ng/mL, n = 6; ApoE = 0.64 ± 0.05 ng/mL, n = 3; DKO = 0.27 ± 0.05, n = 4). Furthemore, the DKO mice presented decrease hepatic expression of the insulin receptor (WT = 0.739 ± 0.083 AU, n = 6; Mas = 0.567 ± 0.115 AU, n = 6; ApoE = 0.702 ± 0.073 AU, n = 6; DKO = 0.321 ± 0.053 AU, n = 6). The oral glucose tolerance test did not differ between groups, as well as serum insulin levels. The liver levels of lipid peroxidation were increased in DKO (WT = 0.58 ± 0.04 μM/g of protein, n = 6; Mas = 0.74 ± 0.09 μM/g of protein, n = 6; ApoE = 0.56 ± 0.01 μM/g of protein, n = 6; DKO = 0.78 ± 0.08 μM/g of protein, n = 6). Consistent with this alteration, histological analysis showed degenerative changes of DKO hepatocytes associated with macro-and microvesicular steatosis, but with few inflammatory infiltrates. The mechanism involved in the development of hepatic steatosis was assessed by Western blotting using primary antibodies to PPAR-α, LXR, FoxO1 S256, glycogen phosphorylase (GP) and glucose 6-phosphatase (G6Pase). The DKO group showed lower levels of hepatic expression of PPAR-α and phosphorylated FoxO1. In addition, the Mas deficiency in ApoE animals significantly increased the expression of LXR. However, no changes were observed in the hepatic expression of GP and G6Pase. In conclusion, our data show that the Mas modulates the activity of key transcriptional factors in hepatic lipid homeostasis.
- © 2012 by American Heart Association, Inc.