Leucine accelerates atherosclerosis through dose-dependent MTOR activation in macrophages

Area of Science:

• Cardiovascular Science
• Metabolic Signaling
• Nutritional Immunology

Background:

• Dietary lipids are known contributors to cardiovascular disease (CVD).
• Dietary protein is often viewed favorably for metabolic health and weight management.
• Emerging epidemiological data suggest a potential CVD risk associated with excessive protein intake.

Purpose of the Study:

• To investigate the atherogenic role of dietary protein and its underlying molecular mechanisms.
• To examine the impact of dietary protein and specific amino acids on macrophage function and autophagy in humans and mice.
• To identify potential therapeutic targets for mitigating protein-induced CVD risk.

Main Methods:

• Murine studies to establish the atherogenic role of dietary protein and macrophage MTORC1 signaling.
• Analysis of human monocytes and macrophages to dissect the MTORC1-autophagy cascade.
• Dose-dependent studies using modulated protein and leucine content in mouse models.
• Assessment of monocyte/macrophage dysfunction and atherosclerosis progression.

Main Results:

• Dietary protein was found to play an atherogenic role by inhibiting protective autophagy pathways via macrophage MTORC1 signaling.
• Leucine was identified as the key amino acid, with concentrations above a specific threshold triggering pathogenic signaling.
• This threshold effect of leucine was confirmed to drive atherosclerosis in mouse models.
• Human monocyte and macrophage studies corroborated the findings from animal models.

Conclusions:

• Dietary leucine, at concentrations exceeding a critical threshold, exerts a pathogenic role in cardiovascular disease.
• Macrophage MTORC1 signaling, activated by leucine, is a central mediator of this process.
• Selective inhibition of macrophage leucine-MTOR signaling presents a promising therapeutic strategy for CVD.