Dietary protein restriction reduces circulating VLDL triglyceride levels via CREBH-APOA5–dependent and –independent mechanisms
J. Humberto Treviño-Villarreal, … , Luigi Fontana, James R. Mitchell
J. Humberto Treviño-Villarreal, … , Luigi Fontana, James R. Mitchell
Published November 2, 2018
Citation Information: JCI Insight. 2018;3(21):e99470. https://doi.org/10.1172/jci.insight.99470.
View: Text | PDF
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

×

Figure 1

Short-term dietary protein restriction reduces circulating TGs independently of total caloric intake via effects on VLDL-TG levels.

Options: View larger image (or click on image) Download as PowerPoint
Short-term dietary protein restriction reduces circulating TGs independe...
B6D2F1 mice were fed the indicated complete (C, 18% protein content) or protein-free (PF, protein replaced with isocaloric sucrose) diet for 1 week prior to analysis. (A) Serum triglyceride (TG) concentrations in mice fed the indicated diet on an ad libitum basis (AL) or restricted daily (CR) by 50% (n = 5/group; 2-way ANOVA with Sidak post-hoc test between the indicated groups. (B) Serum TG in mice on the indicated diet (n = 4–5/group; 2-tailed Student’s t test between diets within fed or fasted state). (C) TG levels in FPLC fractions from pooled plasma samples (n = 5/group; VLDL, very low–density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; HDL, high-density lipoprotein). (D) Serum APOB-100 concentration representative of circulating VLDL particle number (n = 5/group; 2-tailed Student’s t test). (E) TG content of purified VLDL particles expressed per unit APOB-100, indicative of VLDL particle lipidation (n = 3/group; 2-tailed Student’s t test). Data expressed as mean ± SD; *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.