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.

Restriction of essential amino acids dictates the systemic metabolic response to dietary protein dilution

“…Unlike severe protein/ AA restriction, which is not compatible with vitality, moderate DPD promotes longevity in multiple species including flies [7][8][9] , rodents 4,10,11 , and perhaps humans 12 . Furthermore, DPD also affects health-span and preclinical studies have demonstrated that DPD can retard age-related diseases such as cancer 12,13 , type 2 diabetes 14,15 , and dyslipidemia/fatty liver disease 16,17 . Notably, dietary protein intake rates are positively related to type 2 diabetes risk as well as all-cause mortality in humans 18,19 .…”

Restriction of essential amino acids dictates the systemic response to dietary protein dilution

“…However, when individual adipose tissue depots were assessed, both perigonadal and subcutaneous fat depots were lower in male, but not female, mice subjected to dietary AA/EAA restriction ( Fig As dietary protein dilution also affects lipid metabolism 14,17 and the IGF1 axis 12,14 , we also assessed these. Serum triglyceride levels were lower with dietary AA/EAA restriction, and this was more pronounced in male than female mice (Suppl.…”

“…Unlike severe protein/AA restriction, which is not compatible with vitality, moderate DPD promotes longevity in multiple species including flies [7][8][9] , rodents 4,10,11 and perhaps humans 12 . Furthermore, DPD also affects health-span and preclinical studies have demonstrated that DPD can retard age-related disease such as cancer 12,13 , type 2 diabetes 14,15 , and dyslipidemia/fatty liver disease 16,17 . Notably, dietary protein intake rates are positively related to type 2 diabetes risk as well as all-cause mortality in humans 18,19 .…”

“…While metabolic health and longevity pursuant to DPD is likely to involve numerous mechanisms, it was recently demonstrated that DPD promotes metabolic and physiological adaptations via constituent AA 14,20,21 , which is largely mimicked by a genetic deficiency in intestinal and kidney neutral AA transport 22 . In particular, dietary protein or AA restriction promotes such metabolic remodeling and health by the liver-derived hormone fibroblast growth factor 21 (FGF21) 23 , largely by increasing energy expenditure relative to food energy intake 14,17,[24][25][26][27][28][29][30][31][32] . Importantly, DPD also increases FGF21 in humans 14,21,24,33 , and this increase is associated with heightened energy expenditure 33 and improved indices of metabolic health 14 .…”

Blood multiomics reveal insights into population clusters with low prevalence of diabetes, dyslipidemia and hypertension

“…In terms of small molecules, the branched chain amino acid leucine is particularly intriguing: free leucine in the circulation promotes glucose uptake by hepatic cells via myostatin, which in turn inhibits glycogenesis and promotes the synthesis of triglycerides and VLDL [32]. Furthermore, leucine acts as a mTORC1 activator, and in hepatic cells mTORC1 inhibits the CREBH-ApoA5 axis, which leads to blunted ApoA5 production [33]. Thus, a low concentration of leucine in the blood may have a dual effect in the liver-it reduces the production of VLDL/triglycerides yet enhances ApoA5 synthesis and assists in the clearance of VLDL/triglycerides from the circulation.…”