Abstract 462: Low Carbohydrate High Protein (LCHP) Diets Are Atherogenic by Modulating Macrophage Mtorc1-mitophagy Signaling to Accelerate Apoptosis and Plaque Complexity

Abstract

Low carbohydrate high protein (LCHP) diets which are commonly utilized for weight loss have been reported to raise cardiovascular risk. However, the mechanisms underlying this risk are unknown. We first confirm that LCHP diets increase atherosclerotic lesion area with a particular rise in plaque complexity. Mass spectrometry analysis reveals protein ingestion acutely elevates amino acid levels in blood and atherosclerotic plaques with concomitant stimulation of macrophage mTORC1 signaling. This activation is causal as LCHP diet-induced plaque progression is abrogated in macrophage-specific Raptor-null mice. A prominent effect of certain amino acids, such as leucine, on macrophages is the synergistic exacerbation of macrophage apoptosis induced by atherogenic lipids. More specifically, leucine stimulates mTORC1-dependent inhibition of autophagy which hinders the mitophagic removal of dysfunctional and pro-apoptotic mitochondria. This amino acid-mTORC1-autophagy signaling axis is supported in vivo by 1) the absence of reduced atherosclerosis in mice dually deficient in macrophage mTORC1 and autophagy (Raptor/ATG5-/-) and 2) the absence of increased atherosclerosis in macrophage autophagy-deficient (ATG5-/-) mice fed a LCHP diet. Our data provide the first mechanistic details of the deleterious effects of high protein diets on macrophages and atherosclerotic progression. Incorporation of these concepts in clinical studies will be important to define the vascular effects of dietary protein.