In this study, we analysed atherosclerosis in Western diet (WD)-fed Sphk1−/− mice and Sphk2−/− mice, both with an ApoE-deficient background and found that Sphk2−/− mice, but not Sphk1−/− mice, show aggravation of atherosclerosis because of defective autophagic breakdown of LDs in macrophages. This evidence concerns the gene APOE and atherosclerosis.