Abstract Body: The pathogenic role for lipids, especially cholesterol, in atherosclerosis is well established although relevant mechanisms of action continue to be uncovered. Cholesterol has recently been identified as an inducer of mammalian target of rapamycin (mTOR) signaling in cell lines. Our work demonstrating a critical role for amino acids, especially leucine, in promoting atherosclerosis through macrophage mTORC1 activation led us to investigate the impact of cholesterol and dietary lipids in this process. We show LDL cholesterol as well as atherogenic lipids that contain modified cholesterol are potent inducers of macrophage mTORC1 especially in concert with leucine. Cholesterol and leucine synergistically dampen autophagy/mitophagy, resulting in mitochondrial dysfunction and apoptosis in an mTOR-dependent manner. Diet-induced elevations in plasma cholesterol and amino acids provide graded activation of macrophage mTORC1 with concomitant reductions in autophagy in atherosclerotic plaques. This previously unrecognized atherogenic signaling role for cholesterol in macrophages highlights a therapeutically relevant mechanism by which dietary nutrients such as lipids and amino acids can cooperate to drive atherosclerosis.