C5L2 Deficiency Enhances Development of Atherosclerosis in ApoE Knockout Mice

Background: The complement system is important in development of atherosclerosis via regulation of lipid and glucose metabolism as well as inflammation. Aim: The aim of the present study was to further analyze the contribution of C5L2 to the development of atherosclerosis. We proposed that, with DIO feeding, C5L2 deficiency would promote a phenotype that encourages atherosclerosis development. Coupled to ApoE deficiency, double knockout (2KO) mice would show exacerbated atherosclerotic plaque formation. Methods: First, Wildtype (WT) and C5L2-/-(C5L2KO) and subsequently, ApoE-/-(ApoEKO) and C5L2/ApoE double knockout mice were placed on diets inducing obesity (DIO) or standard chow diet for 12 15 weeks. Plasma lipids, glucose, cytokines and hepatic glycogen and lipid contents, mRNA levels and enzyme activities and atherosclerotic plaque size were measured. Results: C5L2KO had increased hepatic glucose oxidation (+90%, p < 0.001), reduced liver glycogen content on chow diet (−34%, p < 0.05) but increased with DIO (+51%, p < 0.05) vs WT. Glucose clearance was delayed in C5L2/ApoE-2KO vs ApoEKO mice with chow (p < 0.0001) and DIO diet (p = 0.0026). C5L2KO mice had increased hepatic lipid content and fatty acid synthesis but decreased lipid oxidation vs WT. Plasma cholesterol was further elevated in C5L2/ApoE-2KO vs ApoEKO with DIO feeding (p < 0.05). Hepatic cytokine expression was increased in C5L2KO mice compared to WT mice. Atherosclerotic plaque size was increased in C5L2/ ApoE-2KO mice compared with apoEKO on chow (p < 0.05) and DIO regimen (p < 0.001). Conclusions: C5L2 disruption worsens glucose and lipid metabolism, increases hepatic and circulating inflammation, and aggravates atherosclerosis.