Identification of a leucine-mediated threshold effect governing macrophage mTOR signalling and cardiovascular risk.
Journal
Nature metabolism
ISSN: 2522-5812
Titre abrégé: Nat Metab
Pays: Germany
ID NLM: 101736592
Informations de publication
Date de publication:
Feb 2024
Feb 2024
Historique:
received:
23
02
2022
accepted:
09
01
2024
medline:
27
2
2024
pubmed:
27
2
2024
entrez:
26
2
2024
Statut:
ppublish
Résumé
High protein intake is common in western societies and is often promoted as part of a healthy lifestyle; however, amino-acid-mediated mammalian target of rapamycin (mTOR) signalling in macrophages has been implicated in the pathogenesis of ischaemic cardiovascular disease. In a series of clinical studies on male and female participants ( NCT03946774 and NCT03994367 ) that involved graded amounts of protein ingestion together with detailed plasma amino acid analysis and human monocyte/macrophage experiments, we identify leucine as the key activator of mTOR signalling in macrophages. We describe a threshold effect of high protein intake and circulating leucine on monocytes/macrophages wherein only protein in excess of ∼25 g per meal induces mTOR activation and functional effects. By designing specific diets modified in protein and leucine content representative of the intake in the general population, we confirm this threshold effect in mouse models and find ingestion of protein in excess of ∼22% of dietary energy requirements drives atherosclerosis in male mice. These data demonstrate a mechanistic basis for the adverse impact of excessive dietary protein on cardiovascular risk.
Identifiants
pubmed: 38409323
doi: 10.1038/s42255-024-00984-2
pii: 10.1038/s42255-024-00984-2
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
359-377Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL125838
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL159461
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK121560
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK056341
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK020579
Pays : United States
Organisme : BLRD VA
ID : I01 BX003415
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR000448
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR000448
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL134635
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL134635
Pays : United States
Informations de copyright
© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
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