Collaborative efforts from Peter Havel, DVM, PhD with UC Davis and the California National Primate Research Center and Andrew Butler, PhD at the St. Louis School University of Medicine indicate that targeting a protein known as angiopoietin-like protein-3 or ANGPTL3 could be helpful for managing cardiovascular disease. Their results showed ANGPTL3 levels increased simultaneously with lipid levels in monkeys fed a high sugar diet. Remarkably, both increases in the protein and lipids in the blood could be prevented if the animals were also provided with a fish oil supplement.

As the leading cause of death in the United States, there are many possible causes of cardiovascular disease. One of the most well-known risk factors of cardiovascular disease is hyperlipidemia, which includes a high level of lipids like triglycerides or cholesterol in the blood. Despite a yearly cost of over $350 billion, scientists and doctors are still looking for new and more effective treatments for reducing cardiovascular risk from hyperlipidemia.

Havel, Butler, and their co-authors designed an experiment to test the effects of a high sugar diet on a particularly interesting protein, ANGPTL3, as well as what happens if a high sugar diet is supplemented with fish oil. Havel and Butler chose ANGPTL3 out of eight similarly structured proteins because of its known role in inhibiting lipases, enzymes in the liver and other tissues responsible metabolizing triglycerides into fatty acids and removing them from the circulation.

For the study, 59 male rhesus macaques consumed flavored fructose-sweetened beverages daily in addition to their regular diet with a subset of these animals receiving a whole fish oil supplement. By supplementing the monkeys’ diet with fructose or high fructose corn syrup, researchers can model symptoms of metabolic syndrome seen in humans, including insulin resistance and hyperlipidemia. Most importantly, the model rapidly increases levels of triglycerides and certain lipoproteins in the blood mirroring human risk factors for cardiovascular disease.

While the current study made it clear that both ANGPTL3 and lipid levels increase in response to a high sugar diet, the exact mechanism linking the two is not yet known. Havel also hopes to clarify exactly how components of fish oil are able to interfere with ANGPTL3 production and increased circulating lipid levels. Understanding these pathways is likely to be informative for developing new interventions for the prevention and treatment of cardiovascular disease.

Interestingly, animals provided a fish oil supplement seemed to be protected from increases in ANGPTL3 and circulating lipid levels normally triggered by a high sugar diet. Havel, Butler and collaborators also showed that inhibiting the production of ANGPTL3 using RNA interference technology resulted in lower levels of a number of lipids and lipoproteins in the circulation. The simultaneous decrease in ANGPTL3 and circulating lipids indicates the protein could be a helpful therapeutic target.

Contributing Authors:
Andrew A. Butler, James L. Graham, Kimber L. Stanhope, So Wong, Sarah Kind, Andrew A. Bremer, Ronald M. Krauss, James Hamilton, and Peter J. Havel

Funding Sources
NIH AT250099, NIH AT003645, American Diabetes Association, CNPRC, NIH UL1 RR024146, NIH HL121324, NIH DK095960, NIH U24 DK092993

Written By Logan Savidge