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 P < 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.