Send to

Choose Destination
JCI Insight. 2018 Nov 2;3(21). pii: 99470. doi: 10.1172/jci.insight.99470.

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

Author information

Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
Sabri Ülker Center for Nutrient, Genetic, and Metabolic Research, Boston, Massachusetts, USA.
Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University, Munich, Germany.
German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.
Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA.
Division of Vascular and Endovascular Surgery, Department of Surgery, and.
Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
Division of Sleep Medicine, Department of Medicine, Harvard Medical School (HMS), Boston, Massachusetts, USA.
Department of Neurosurgery, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Department of Surgery, HMS, Boston, Massachusetts, USA.
Division of Urology, Washington University School of Medicine, St. Louis, Missouri, USA.
Dana Farber Cancer Institute/HMS Rodent Histopathology Core Facility, HMS, Boston, Massachusetts, USA.
Department for Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Germany.
Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
School of Medicine and Charles Perkins Centre, University of Sydney, Sydney, Australia.


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.


Lipoproteins; Metabolism

Supplemental Content

Full text links

Icon for American Society for Clinical Investigation Icon for PubMed Central
Loading ...
Support Center