Fructose-induced hypertriglyceridemia in rhesus macaques is attenuated with fish oil or ApoC3 RNA interference.

Dyslipidemia and insulin resistance are significant adverse outcomes of consuming high-sugar diets. Conversely, dietary fish oil (FO) reduces plasma lipids. Diet-induced dyslipidemia in a rhesus model better approximates the pathophysiology of human metabolic syndrome (MetS) than rodent models. Here, we investigated relationships between metabolic parameters and hypertriglyceridemia in rhesus macaques consuming a high-fructose diet (n = 59) and determined the effects of FO supplementation or RNA interference (RNAi) on plasma ApoC3 and triglyceride (TG) concentrations. Fructose supplementation increased body weight, fasting insulin, leptin, TGs, and large VLDL particles and reduced adiponectin concentrations (all < 0.001). In multiple regression analyses, increased plasma ApoC3 was the most consistent and significant variable related to diet-induced hypertriglyceridemia. FO supplementation, which attenuated increases of plasma TG and ApoC3 concentrations, reversed fructose-induced shifts of lipoprotein particle size toward IDL and VLDL, a likely mechanism contributing to beneficial metabolic effects, and reduced hepatic expression of genes regulated by the SREBP pathway, particularly acetyl-CoA carboxylase. Furthermore, RNAi-mediated ApoC3 inhibition lowered plasma TG concentrations in animals with diet-induced hypertriglyceridemia. In summary, ApoC3 is an important independent correlate of TG-rich lipoprotein concentrations in rhesus macaques consuming a high-fructose diet. ApoC3 is a promising therapeutic target for hypertriglyceridemia in patients with MetS and diabetes.