Angiopoietin-like protein 8 accelerates atherosclerosis in ApoE-/- mice

Background and aims: Angiopoietin-like protein 8 (ANGPTL8) is a hormone involved in regulating lipid metabolism. Patients with coronary artery disease have markedly higher plasma levels of ANGPTL8 than controls; however, the role of ANGPTL8 in atherosclerosis has not been explored. Therefore, we explored the effects of ANGPTL8 on atherosclerosis development in a mouse model. Methods: We induced experimental atherosclerosis in ApoE(-/-) mice ANGPTL8-knockdown. and ANGPTL8-overexpression ApoE(-/-) mice. We also explored the mechanism using ANGPTL8-overexpression macrophages. Results: ANGPTL8 expression was increased in human and mouse atherosclerotic lesions. ANGPTL8 overexpression promoted the development of atherosclerosis whereas ANGPTL8 knockdown protected against atherosclerosis. Immunofluorescence co-staining results showed that ANGPTL8 was expressed in macrophages in atherosclerotic plaques. Compared with wild type cells, ANGPTL8-overexpressing macrophages, including bone marrow-derived macrophages and Raw 264.7 macrophages, showed enhanced foam cell formation and increased accumulation of cholesterol that was induced by increased uptake and decreased effiux of cholesterol. The results of this study also showed that ANGPTL8 induced the expression of CD36 and scavenger receptor (SR)-A, and inhibited the expression of SR-BI. Conclusions: Our findings demonstrate an unanticipated role of ANGPTL8 in the development of atherosclerosis and regulation of foam cell formation. ANGPTL8 may be a promising new target for atherosclerosis.