Abstract Body: Diet and nutrients are critical factors in cardiovascular disease (CVD), the leading cause of mortality in the U.S. While observational evidence suggests plant proteins offer superior health benefits over animal proteins, the underlying mechanisms regulating their differential effects on atherosclerosis remain poorly understood. Building on our findings that leucine drives macrophage mTORC1 signaling and atherogenesis, we hypothesized that high-animal protein diets—but not high-plant protein diets—selectively activate this pathway to promote atherogenesis.

To test our hypothesis, we investigated the acute effects of various animal proteins (chicken, egg, beef, and casein) versus plant proteins (soy, rice, and pea) on monocyte mTORC1 activation in mice via oral gavage (n=5 each group). Long-term atherogenic effects, including plaque burden and lesion complexity, were evaluated in ApoE-null mice feeding atherogenic diets with different protein resources (n=8 each group). For translational validation, a clinical trial measured monocyte mTORC1 signaling in participants following meals containing graded amounts of either plant or animal proteins (n=8 each group).

Despite similar total leucine content, animal proteins induced a significantly greater postprandial rise in plasma leucine levels in mice compared to plant proteins. Consequently, animal protein gavage triggered more robust mTORC1 activation in circulating monocytes. Supplementing plant proteins with leucine eliminated this disparity, confirming leucine as the dominant driver of protein-induced mTORC1 signaling. These findings were mirrored in human subjects: high-animal protein meals significantly increased plasma leucine and monocyte mTORC1 activation, whereas high-plant protein meals resulted in minimal changes. Furthermore, ApoE-null mice fed a high-plant protein diet exhibited dramatically reduced macrophage mTORC1 signaling, plaque size, and complexity compared to those on a high-animal protein diet which were completely reversed when plant proteins were supplemented with leucine.

In conclusion, utilizing murine models and human clinical studies, we demonstrate the atheroprotective benefits of dietary plant proteins. Moreover, we establish the first mechanistic framework explaining how animal protein contributes to disproportionate cardiovascular risks, providing a foundation for future nutritional guidelines.