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

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Dietary protein restriction reduces circulating VLDL triglyceride levels via CREBH-APOA5-dependent and -independent mechanisms. / Treviño-Villarreal, J Humberto; Reynolds, Justin S; Bartelt, Alexander; Langston, P Kent; MacArthur, Michael R; Arduini, Alessandro; Tosti, Valeria; Veronese, Nicola; Bertozzi, Beatrice; Brace, Lear E; Mejia, Pedro; Trocha, Kaspar; Kajitani, Gustavo S; Longchamp, Alban; Harputlugil, Eylul; Gathungu, Rose; Bird, Susan S; Bullock, Arnold D; Figenshau, Robert S; Andriole, Gerald L; Thompson, Andrew; Heeren, Jöerg; Ozaki, C Keith; Kristal, Bruce S; Fontana, Luigi; Mitchell, James R.

in: JCI INSIGHT, Jahrgang 3, Nr. 21, 02.11.2018.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Treviño-Villarreal, JH, Reynolds, JS, Bartelt, A, Langston, PK, MacArthur, MR, Arduini, A, Tosti, V, Veronese, N, Bertozzi, B, Brace, LE, Mejia, P, Trocha, K, Kajitani, GS, Longchamp, A, Harputlugil, E, Gathungu, R, Bird, SS, Bullock, AD, Figenshau, RS, Andriole, GL, Thompson, A, Heeren, J, Ozaki, CK, Kristal, BS, Fontana, L & Mitchell, JR 2018, 'Dietary protein restriction reduces circulating VLDL triglyceride levels via CREBH-APOA5-dependent and -independent mechanisms', JCI INSIGHT, Jg. 3, Nr. 21. https://doi.org/10.1172/jci.insight.99470

APA

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., ... Mitchell, J. R. (2018). Dietary protein restriction reduces circulating VLDL triglyceride levels via CREBH-APOA5-dependent and -independent mechanisms. JCI INSIGHT, 3(21). https://doi.org/10.1172/jci.insight.99470

Vancouver

Treviño-Villarreal JH, Reynolds JS, Bartelt A, Langston PK, MacArthur MR, Arduini A et al. Dietary protein restriction reduces circulating VLDL triglyceride levels via CREBH-APOA5-dependent and -independent mechanisms. JCI INSIGHT. 2018 Nov 2;3(21). https://doi.org/10.1172/jci.insight.99470

Bibtex

@article{3a11aa3932cd47fbb0f2be652644c827,
title = "Dietary protein restriction reduces circulating VLDL triglyceride levels via CREBH-APOA5-dependent and -independent mechanisms",
abstract = "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.",
keywords = "Journal Article",
author = "Trevi{\~n}o-Villarreal, {J Humberto} and Reynolds, {Justin S} and Alexander Bartelt and Langston, {P Kent} and MacArthur, {Michael R} and Alessandro Arduini and Valeria Tosti and Nicola Veronese and Beatrice Bertozzi and Brace, {Lear E} and Pedro Mejia and Kaspar Trocha and Kajitani, {Gustavo S} and Alban Longchamp and Eylul Harputlugil and Rose Gathungu and Bird, {Susan S} and Bullock, {Arnold D} and Figenshau, {Robert S} and Andriole, {Gerald L} and Andrew Thompson and J{\"o}erg Heeren and Ozaki, {C Keith} and Kristal, {Bruce S} and Luigi Fontana and Mitchell, {James R}",
year = "2018",
month = nov,
day = "2",
doi = "10.1172/jci.insight.99470",
language = "English",
volume = "3",
journal = "JCI INSIGHT",
issn = "2379-3708",
publisher = "The American Society for Clinical Investigation",
number = "21",

}

RIS

TY - JOUR

T1 - Dietary protein restriction reduces circulating VLDL triglyceride levels via CREBH-APOA5-dependent and -independent mechanisms

AU - Treviño-Villarreal, J Humberto

AU - Reynolds, Justin S

AU - Bartelt, Alexander

AU - Langston, P Kent

AU - MacArthur, Michael R

AU - Arduini, Alessandro

AU - Tosti, Valeria

AU - Veronese, Nicola

AU - Bertozzi, Beatrice

AU - Brace, Lear E

AU - Mejia, Pedro

AU - Trocha, Kaspar

AU - Kajitani, Gustavo S

AU - Longchamp, Alban

AU - Harputlugil, Eylul

AU - Gathungu, Rose

AU - Bird, Susan S

AU - Bullock, Arnold D

AU - Figenshau, Robert S

AU - Andriole, Gerald L

AU - Thompson, Andrew

AU - Heeren, Jöerg

AU - Ozaki, C Keith

AU - Kristal, Bruce S

AU - Fontana, Luigi

AU - Mitchell, James R

PY - 2018/11/2

Y1 - 2018/11/2

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1172/jci.insight.99470

DO - 10.1172/jci.insight.99470

M3 - SCORING: Journal article

C2 - 30385734

VL - 3

JO - JCI INSIGHT

JF - JCI INSIGHT

SN - 2379-3708

IS - 21

ER -