Role of ASGR1 on obesity and metabolic syndrome

Abstract

Background: Obesity-related fat accumulation is linked to the metabolic syndrome and increases the risk of CVD by involving FFA, insulin resistance, and inflammation. Taking into account the findings from the third chapter, our goal was to assess the potential role of ASGR1 in metabolic reprogramming and immunoinflammatory state during obesity. Methods: After 20 weeks of high fat diet, flow cytometry, proteomics, lipid profile, glucose tolerance, and insulin tolerance were assessed in WT and ASGR1-/- mice (HFD). Additionally, metabolic parameters such as oxygen consumption, CO2 production, and food intake were measured during the diet. Results: After 20 weeks of HFD, the ASGR1−/− mice displayed a significant reduction in the circulating monocytes compared to WT. The body weight and food intake were comparable in between two groups. The adipose tissue VAT was significantly increased in ASGR1-/- compared to WT mice (WT 3.2%±0.8%, ASGR1-/- 4.7%±1.2%, P-value<0.001). The proteomics revealed, n=3412 proteins were aligned from which 624 proteins were significantly differentially expressed on the liver of ASGR1-/- and WT mice under HFD. From prediction analysis the significant proteins that were increase in the liver of ASGR1-/- mice were necrosis, apoptosis, and inflammation compared to the WT. Additionally, a significant downregulation in proteins protein expression involved in fatty acid synthesis and fatty acid uptake, except the increased expression of fatty acid coenzyme A ligase (FATP5), which belongs to very long chain acyl-CoA synthetases, capable mediation the transport of long chain fatty acids. Conclusion: Our findings indicate that ASGR1 deficiency causes increased inflammation and changes in metabolic pathways when subjected to HFD. This can also have an impact on the synthesis of apolipoproteins secreted in plasma.