Abstract P147: Dietary Protein Elicits A Leucine-mediated Threshold Effect On Monocyte/macrophage Mtorc1-autophagy Signaling Resulting In Elevated Cardiovascular Risk

High-protein intake is common in Western societies and generally considered healthy. However, results from some epidemiological studies suggest elevated protein intake is associated with increased risk for ischemic cardiovascular diseases. In addition, results from studies conducted in mice show that a high protein, compared with a standard Western diet, increases atherosclerosis burden and lesion complexity. The adverse effect of protein ingestion on plaque biology in mice is mediated by amino acid-mammalian target of rapamycin (mTOR)-dependent inhibition of autophagy in macrophages. Here, we evaluate the effect of graded amounts of protein ingestion on this amino acid-mTORC1-autophagy mechanism in human monocytes/macrophages and identify leucine as the key amino acid responsible for activating mTORC1 in macrophages. We describe the presence of a threshold effect of high protein intake on this deleterious signaling pathway wherein protein content greater than about 22% of total energy, which is consumed by nearly 1/4 th of the population in Western societies, acutely activates mTORC1 signaling in monocytes/macrophages. Furthermore, we identify leucine as the critical amino acid modulator and threshold indicator, capable of the dose-dependent mTORC1 activation and downstream functional effects. Finally, by designing specific mouse diets with protein contents mimicking graded levels of protein ingestion in our study participants, we demonstrate the presence of a dietary protein threshold effect in driving atherosclerosis in mouse models. These data demonstrate the potential deleterious impact of excessive protein intake on macrophages and atherosclerotic plaque progression.