Dietary protein restriction reduces circulating VLDL triglyceride levels via CREBH-APOA5-dependent and -independent mechanisms.

Détails

ID Serval
serval:BIB_8692F268FC17
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Dietary protein restriction reduces circulating VLDL triglyceride levels via CREBH-APOA5-dependent and -independent mechanisms.
Périodique
JCI insight
Auteur⸱e⸱s
Treviño-Villarreal J.H., Reynolds J.S., Bartelt A., Langston P.K., MacArthur M.R., Arduini A., Tosti V., Veronese N., Bertozzi B., Brace L.E., Mejia P., Trocha K., Kajitani G.S., Longchamp A., Harputlugil E., Gathungu R., Bird S.S., Bullock A.D., Figenshau R.S., Andriole G.L., Thompson A., Heeren J., Ozaki C.K., Kristal B.S., Fontana L., Mitchell J.R.
ISSN
2379-3708 (Electronic)
ISSN-L
2379-3708
Statut éditorial
Publié
Date de publication
02/11/2018
Peer-reviewed
Oui
Volume
3
Numéro
21
Langue
anglais
Notes
Publication types: Clinical Trial ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Résumé
Hypertriglyceridemia is an independent risk factor for cardiovascular disease. Dietary interventions based on protein restriction (PR) reduce circulating triglycerides (TGs), but underlying mechanisms and clinical relevance remain unclear. Here, we show that 1 week of a protein-free diet without enforced calorie restriction significantly lowered circulating TGs in both lean and diet-induced obese mice. Mechanistically, the TG-lowering effect of PR was due, in part, to changes in very low-density lipoprotein (VLDL) metabolism both in liver and peripheral tissues. In the periphery, PR stimulated VLDL-TG consumption by increasing VLDL-bound APOA5 expression and promoting VLDL-TG hydrolysis and clearance from circulation. The PR-mediated increase in Apoa5 expression was controlled by the transcription factor CREBH, which coordinately regulated hepatic expression of fatty acid oxidation-related genes, including Fgf21 and Ppara. The CREBH-APOA5 axis activation upon PR was intact in mice lacking the GCN2-dependent amino acid-sensing arm of the integrated stress response. However, constitutive hepatic activation of the amino acid-responsive kinase mTORC1 compromised CREBH activation, leading to blunted APOA5 expression and PR-recalcitrant hypertriglyceridemia. PR also contributed to hypotriglyceridemia by reducing the rate of VLDL-TG secretion, independently of activation of the CREBH-APOA5 axis. Finally, a randomized controlled clinical trial revealed that 4-6 weeks of reduced protein intake (7%-9% of calories) decreased VLDL particle number, increased VLDL-bound APOA5 expression, and lowered plasma TGs, consistent with mechanistic conservation of PR-mediated hypotriglyceridemia in humans with translational potential as a nutraceutical intervention for dyslipidemia.
Mots-clé
Animals, Apolipoprotein A-V, Apolipoproteins/metabolism, Cyclic AMP Response Element-Binding Protein, Diet, Protein-Restricted/adverse effects, Diet, Protein-Restricted/methods, Female, Humans, Hydrolysis, Hypertriglyceridemia/complications, Hypertriglyceridemia/epidemiology, Lipid Metabolism, Lipoproteins, VLDL/blood, Lipoproteins, VLDL/metabolism, Liver/metabolism, Liver/pathology, Male, Mechanistic Target of Rapamycin Complex 1/metabolism, Mice, Protein-Serine-Threonine Kinases/deficiency, Protein-Serine-Threonine Kinases/metabolism, Randomized Controlled Trials as Topic, Risk Factors, Triglycerides/blood, Triglycerides/metabolism, Lipoproteins, Metabolism
Pubmed
Web of science
Open Access
Oui
Financement(s)
Fonds national suisse / Carrières / P1LAP3_158895
Création de la notice
07/03/2021 12:36
Dernière modification de la notice
08/03/2021 6:26
Données d'usage