High-protein diets increase cardiovascular risk by activating macrophage mTOR to suppress mitophagy

Abstract

High protein diets are commonly utilized for weight loss, yet have been reported to raise cardiovascular risk. The mechanisms underlying this risk are unknown. Here, we show that dietary protein drives atherosclerosis and lesion complexity. Protein ingestion acutely elevates amino acid levels in blood and atherosclerotic plaques, stimulating macrophage mTOR signaling. This is causal in plaque progression as the effects of dietary protein are abrogated in macrophage-specific Raptor-null mice. Mechanistically, we find amino acids exacerbate macrophage apoptosis induced by atherogenic lipids, a process that involves mTORC1-dependent inhibition of mitophagy, accumulation of dysfunctional mitochondria, and mitochondrial apoptosis. Using macrophagespecific mTORC1-and autophagy-deficient mice we confirm this amino acid-mTORC1autophagy signaling axis in vivo. Our data provide the first insights into the deleterious impact of Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

RETRACTED: Molecular Perspectives of Mitophagy in Myocardial Stress: Pathophysiology and Therapeutic Targets

“…The activation of mitophagy through astaxanthin administration was found to protect against hypertension-induced vascular remodeling by reducing mitochondrial oxidative stress and inhibiting mitochondrial fission in vascular smooth muscle cells ( Chen et al, 2020b ). High-protein diet consumption (a common weight-loss practice) was reported to increase cardiovascular risk by repressing mitophagy and inducing the mammalian target of rapamycin pathway ( Zhang et al, 2020 ).…”

Nutraceuticals Targeting Generation and Oxidant Activity of Peroxynitrite May Aid Prevention and Control of Parkinson’s Disease

“…Increased cellular levels of leucine, arginine, and of the methionine metabolite S-adenosylmethionine boost mTORC1 activity by suppressing mechanisms which turn off this activity [246][247][248][249][250][251][252]. Crucially, mTORC1 acts to inhibit expression of PINK1 at the transcriptional level; this effect might be mediated, in part, by transcriptional repression of FOXO1a, which binds to the promoter of the PINK1 gene and promotes its transcription [253][254][255]. Since PINK1 is required for recruitment of Parkin to damaged depolarized mitochondria, mTORC1 functions to suppress mitophagy [253][254][255].…”

“…Crucially, mTORC1 acts to inhibit expression of PINK1 at the transcriptional level; this effect might be mediated, in part, by transcriptional repression of FOXO1a, which binds to the promoter of the PINK1 gene and promotes its transcription [253][254][255]. Since PINK1 is required for recruitment of Parkin to damaged depolarized mitochondria, mTORC1 functions to suppress mitophagy [253][254][255]. Conversely, low-protein diets can be expected to boost mitophagy by concurrent activation of GCN2 and de-activation of mTORC1.…”

Is protein the forgotten ingredient: Effects of higher compared to lower protein diets on cardiometabolic risk factors. A systematic review and meta-analysis of randomised controlled trials

“…High protein diets have been promoted for decades for weight loss purposes, prevention of obesity and its metabolic consequences, yet have been documented to increase the risk of cardiovascular disease (CVD) mortality [11,12] and type 2 diabetes (T2D) [13]. High protein diets have been reported to promote atherogenesis in animal models [14]. Mechanistically, protein ingestion acutely increases blood amino acid concentrations, circulating monocytes, and tissue macrophages, including those residing in the atherosclerotic plaque.…”

“…Mechanistically, protein ingestion acutely increases blood amino acid concentrations, circulating monocytes, and tissue macrophages, including those residing in the atherosclerotic plaque. This, in turn, leads to acute elevation of macrophage mechanistic target of rapamycin (mTOR) signalling, causing plaque progression [14]. High protein intake is also reported to increase insulin-like growth factor-1 (IGF-1) and to activate the mTOR-S6 kinase signalling pathway, while protein deficiency is sensed by unloaded transfer ribonucleic acid (tRNA), activating the protective general amino acid control nonderepressible-2 (GCN2) kinase pathway, which induces an activating transcription factor4 (ATF4) mediated protective integrated stress response [15].…”