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

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.

Authors

J. Humberto Treviño-Villarreal, Justin S. Reynolds, Alexander Bartelt, P. Kent Langston, Michael R. MacArthur, Alessandro Arduini, Valeria Tosti, Nicola Veronese, Beatrice Bertozzi, Lear E. Brace, Pedro Mejia, Kaspar Trocha, Gustavo S. Kajitani, Alban Longchamp, Eylul Harputlugil, Rose Gathungu, Susan S. Bird, Arnold D. Bullock, Robert S. Figenshau, Gerald L. Andriole, Andrew Thompson, Jöerg Heeren, C. Keith Ozaki, Bruce S. Kristal, Luigi Fontana, James R. Mitchell

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Figure 8

Moderate protein restriction increases APOA5 expression and reduces TG levels in mice and humans.

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Moderate protein restriction increases APOA5 expression and reduces TG l...
(A–F) Titration of protein restriction (18%–0% protein replaced with isocaloric sucrose) in B6D2F1 mice for 1 week. Immunoblot analyses of (A) CREBH full-length (FL) and cleaved form (CF), (B) APOA5, (C) PERK phosphorylation, and (D) ATF4 protein expression in whole liver extracts. For quantitation at right of each blot, samples were binned in 3 groups based on the level of dietary protein (high, 18%–10%; medium, 8%–6%; low, 4%–0%; n = 4–6/group; 1-way ANOVA with Dunnett post-hoc test compared with the high protein group). (E and F) Serum FGF21 (E) and TG (F) levels; 1-way ANOVA with Dunnett post-hoc test compared with the 18% protein group. (G–J) Effect of a low-protein diet in humans. Patients were randomized to control or protein restricted (PR, 7%–9% of energy from protein) diets; blood samples were taken before or after 4–6 weeks on the indicated diet (n = 19 per group; paired t test comparing parameter before and after diet). (G) Plasma APOB-100 concentration representative of circulating VLDL particle number. (H) Plasma APOA5. (I) VLDL-bound APOA5 levels expressed as the ratio of plasma APOA5 to APOB-100. (J) Plasma TG levels. Data expressed as mean ± SD; *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.001.