Role of angiopoietin-like protein 3 in sugar-induced dyslipidemia in rhesus macaques: suppression by fish oil or RNAi.

Angiopoietin-like protein 3 (ANGPTL3) inhibits lipid clearance and is a promising target for therapies for managing cardiovascular disease. Here we investigated the effect of a high-sugar (fructose) diet on circulating ANGPTL3 concentrations in rhesus macaques. Plasma ANGPTL3 concentrations increased ~30-40% after 1 and 3 months of a high-fructose diet (both p<0.001 versus baseline). During fructose-induced metabolic dysregulation, plasma ANGPTL3 concentrations were positively correlated with circulating indices of insulin resistance (assessed with fasting insulin and the homestatic model assessment of insulin resistance [HOMA-IR]), hypertriglyceridemia, adiposity (assessed as leptin) and systemic inflammation (C-reactive peptide [CRP]), and negatively with plasma levels of the insulin-sensitizing hormone adropin. Multiple regression analyses identified a strong association between circulating APOC3 and ANGPTL3 concentrations. Higher baseline plasma levels of both ANGPTL3 and APOC3 were associated with an increased risk for fructose-induced insulin resistance. Fish oils previously shown to prevent insulin resistance and hypertriglyceridemia in this model prevented increases of ANGPTL3 in this model without affecting systemic inflammation (increased plasma CRP and interleukin-6 concentrations). ANGPTL3 RNAi lowered plasma concentrations of ANGPTL3, TG, cholesterol (VLDL-C), APOC3 and APOE, decreases consistent with reduced risk of atherosclerosis. In summary, dietary sugar-induced increases in circulating ANGPTL3 concentrations after metabolic dysregulation correlated positively with leptin levels, HOMA-IR and dyslipidemia. Targeting ANGPTL3 expression with RNAi inhibited dyslipidemia by lowering plasma TG, VLDL-C APOC3, and APOE levels in rhesus macaques.