Abstract 3055: Cholesterol And Amino Acids Derived From Dietary Sources Drive Atherosclerosis Via Synergistic Activation Of Macrophage Mtorc1 Signaling.

The pathogenic role for lipids, especially cholesterol, in atherosclerosis is well established although relevant mechanisms of action continue to be uncovered. Recent studies linking cholesterol, cholesterol sensing, and the induction of proatherogenic mammalian target of rapamycin (mTOR) signaling is one area with significant therapeutic potential. Our previous studies demonstrated a critical role for amino acids, especially leucine, derived from dietary protein in promoting plaque progression through activation of macrophage mTORC1. We thus aimed to understand the role of cholesterol in macrophage mTOR signaling, its relation to amino acid-mediated effects, and cooperation between dietary lipids and protein in plaque mTOR activation and atherosclerosis. Here, we show LDL cholesterol as well as atherogenic lipids containing modified cholesterol (7-Ketocholesterol and oxLDL) are potent inducers of macrophage mTORC1 especially inconcert with leucine. Importantly, cholesterol and leucine synergistically dampen autophagy/mitophagy, resulting in mitochondrial dysfunction and apoptosis, a process which is completely mTORC1-dependent. In vivo, we find lesional macrophage mTORC1 is stimulated by elevation of plasma cholesterol in ApoE-null mice (n=8-10 per group) fed a Western Diet, while increases in circulating amino acids and cholesterol as a result of diets enriched in protein and lipids lead to mTORC1 hyperactivation and concomitant reduction in autophagy. In conclusion, our study identifies a previously unrecognized signaling role for cholesterol in macrophages and highlights a unique and therapeutically relevant mechanism by which dietary nutrients such as lipids and amino acids can cooperate to drive atherosclerosis.