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

Nature Metabolism
Xiangyu ZhangBabak Razani

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 macrophage-specific mTORC1- and autophagy-deficient mice we confirm this amino acid-mTORC1-autophagy signaling axis in vivo. Our data provide the first insights into the deleterious impact of excessive protein ingestion on macrophages and atherosclerotic progression. Incorporation of these concepts in clinical studies will be important to define the vascular effects of protein-based weight loss regimens.

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Citations

Jul 21, 2020·Archives of Physiology and Biochemistry·Murilo Esteves NogueiraJeeser Alves Almeida
Jul 23, 2020·Nature Metabolism·Hanrui Zhang, Muredach P Reilly
May 28, 2020·International Journal of Molecular Sciences·Mark F McCarty, Aaron Lerner
Sep 2, 2020·Current Opinion in Clinical Nutrition and Metabolic Care·Alan Fappi, Bettina Mittendorfer
Nov 10, 2020·Molecular Aspects of Medicine·Adélie DumontLaurent Yvan-Charvet
Feb 2, 2021·Endocrine Reviews·Adil Rasheed, Katey J Rayner
Jul 8, 2021·Journal of Cardiovascular Pharmacology·Yibo LiGuoan Zhao
Jul 28, 2021·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·So Yeong Cheon, KyoungJoo Cho
Aug 31, 2021·The EMBO Journal·Daniel J KlionskyFederico Pietrocola

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Methods Mentioned

BETA
genetic modifications
fluorescence-activated cell sorting
flow cytometry
fluorescence microscopy
FACS
dissection
genotyping
FCS
fluorescence imaging
Assay

Software Mentioned

ImageJ
FlowJo
ZEN microscope

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