Distinct Roles of apoE Receptor-2 Cytoplasmic Domain Splice Variants in Cardiometabolic Disease Modulation

Background/Objectives: Apolipoprotein E receptor-2 (apoER2) exists in various alternatively spliced forms, including variants that express apoER2 with or without exon 19 in the cytoplasmic domain. This study compared vascular response to endothelial denudation, as well as diet-induced atherosclerotic and metabolic diseases, between genetically modified mice that exclusively expressed the apoER2 splice variant with or without exon 19 to determine the impact of apoER2 exon 19 motif in cardiometabolic disease modulation. Methods: Vascular response to injury was assessed by measuring neointima area of the carotid arteries after endothelial denudation. The genetically modified mice were also fed a high-fat high-cholesterol diet for 16 weeks for the determination of body weight gain, glucose and insulin levels, glucose tolerance and insulin secretion. Additionally, adipose tissue inflammation was assessed by analysis of adipose gene expression, and atherosclerosis was characterized by measuring fatty lesion size in the whole aorta, as well as in the aortic roots. Results: The results showed that whereas the expression of either splice variant is sufficient to impede denudation-induced fibrotic neointima formation and complex necrotic atherosclerotic lesions, the expression of the apoER2 splice variant containing exon 19 is necessary for the complete protection of injury-induced neointima formation in the vessel wall. However, exclusive expression of either apoER2 cytoplasmic splice variant does not influence the early phase of atherogenesis. Additionally, the exclusive expression of apoER2 without exon 19 promotes adipocyte inflammation and accelerates diet-induced insulin resistance and glucose intolerance. Conclusions: These results indicate that the apoER2 cytoplasmic variants have distinct and cell type-specific roles in influencing cardiometabolic disease development.