Overwhelming evidence indicates that pharmacological AMPK activation (polyphenol S17834, A-769662, AICAR, metformin, and IMM-H007) attenuates atherosclerosis development in diet-induced apolipoprotein E deficient (ApoE-/-) or LDL receptor-deficient (LDLR-/-) mice, which can be explained by their beneficial effects on hepatic lipid accumulation, hyperlipidemia, insulin resistance, and autophagy. Here, APOE is linked to atherosclerosis.