Abstract 384: Low Carbohydrate High Protein (LCHP) Diets are Atherogenic by Supplying Excess Amino Acids to Alter the Macrophage mTORC1-Autophagy Signaling Axis

Abstract

Low carbohydrate high protein (LCHP) diets are commonly used in weight loss programs. However, the overall health benefits of such regimens are controversial with recent studies even suggesting an increased cardiovascular risk in certain populations. A few reports in animal models corroborate these concerns demonstrating increased LCHP-induced atherosclerosis. Interestingly, the downstream sequelae of such diets on tissues and cellular signaling are largely inferred with relevant mechanisms undefined. We first confirmed in the ApoE-null mouse model that LCHP diets are indeed atherogenic with the development of complex lesions. Using mass spectrometry, we find high protein feeding not only increases serum amino acid levels but increases amino acid load to tissues including the spleen and aorta with resultant activation of the mTORC1 signaling pathway particularly in macrophages. The involvement of mTORC1 is clearly causal as the atherogenic effect of LCHP-feeding is abrogated in macrophage-specific Raptor-null mice. Further mechanistic evaluation of the effects of amino acids on macrophages reveals dichotomous roles on a predominant mTORC1 target, autophagy. Certain amino acids such as Leucine potently activate mTORC1 via recruitment to lysosome and in turn suppress autophagy via ULK1 phosphorylation, whereas others such as glutamine act indirectly by downregulating the transcription of autophagy chaperones including p62/SQSTM1. This combined suppressive effect on autophagy leads to macrophage inflammasome activation and IL-1β release, accumulation of deleterious protein aggregates, and increased cell death. The in vivo relevance of this LCHP-amino acid-mTORC1-autophagy axis is supported by 1) the absence of increased atherosclerosis in macrophage autophagy-deficient (ATG5-/-) mice fed a LCHP diet, and 2) the absence of reduced atherosclerosis in mice dually deficient in macrophage mTORC1 and autophagy (Raptor/ATG5-/-). Our data provide the first mechanistic details of the deleterious effects of high protein diets on macrophages and the development of atherosclerosis. Incorporation of these concepts in clinical studies will be important to define the vascular effects of dietary protein.