High-protein diets increase cardiovascular risk by activating macrophage mTOR to suppress mitophagy.
Journal
Nature metabolism
ISSN: 2522-5812
Titre abrégé: Nat Metab
Pays: Germany
ID NLM: 101736592
Informations de publication
Date de publication:
01 2020
01 2020
Historique:
entrez:
5
3
2020
pubmed:
5
3
2020
medline:
5
3
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32128508
doi: 10.1038/s42255-019-0162-4
pmc: PMC7053091
mid: NIHMS1546635
pii: 10.1038/s42255-019-0162-4
doi:
Substances chimiques
mTOR protein, mouse
EC 2.7.1.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Pagination
110-125Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL125838
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK115867
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL134635
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL143431
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL107594
Pays : United States
Organisme : NIGMS NIH HHS
ID : P41 GM103422
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK020579
Pays : United States
Organisme : BLRD VA
ID : I01 BX004235
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK118333
Pays : United States
Organisme : BLRD VA
ID : I01 BX003415
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK056341
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL116626
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA218578
Pays : United States
Commentaires et corrections
Type : ErratumIn
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