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

Abstract

Angiopoietin-like protein 3 (ANGPTL3) inhibits lipid clearance and is a promising target for managing cardiovascular disease. Here we investigated the effects of a high-sugar (high-fructose) diet on circulating ANGPTL3 concentrations in rhesus macaques. Plasma ANGPTL3 concentrations increased ∼30% to 40% after 1 and 3 months of a high-fructose diet (both P < 0.001 vs. baseline). During fructose-induced metabolic dysregulation, plasma ANGPTL3 concentrations were positively correlated with circulating indices of insulin resistance [assessed with fasting insulin and the homeostatic model assessment of insulin resistance (HOMA-IR)], hypertriglyceridemia, adiposity (assessed as leptin), and systemic inflammation [C-reactive peptide (CRP)] and negatively correlated 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 oil previously shown to prevent insulin resistance and hypertriglyceridemia in this model prevented increases of ANGPTL3 without affecting systemic inflammation (increased plasma CRP and interleukin-6 concentrations). ANGPTL3 RNAi lowered plasma concentrations of ANGPTL3, triglycerides (TGs), VLDL-C, APOC3, and APOE. These decreases were consistent with a reduced risk of atherosclerosis. In summary, dietary sugar-induced increases of 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 TGs, VLDL-C, APOC3, and APOE levels in rhesus macaques.

Targeting angiopoietin‐like 3 in atherosclerosis: From bench to bedside

“…A recent study by Butler et al explored the effects of suppressing Angptl3 expression with RNAi on lipid metabolism in rhesus macaques 108 . The results revealed that Angptl3 RNAi reduced the plasma levels of TG by 50%, HDL‐C by 52% and LDL‐C by 42.3% 108 . Consistent with this study, a study conducted with RNAi silencing of Angptl3 in mouse liver revealed that Angptl3 deficiency led to lower LDL‐C, TG and HDL‐C 71 .…”

“…This study provided a potential model strategy with which to treat dyslipidaemic patients. 83 108 The results revealed that Angptl3 RNAi reduced the plasma levels of TG by 50%, HDL-C by 52% and LDL-C by 42.3%. 108 Consistent with this study, a study conducted with RNAi silencing of Angptl3 in mouse liver revealed that Angptl3 deficiency led to lower LDL-C, TG and HDL-C. 71 ARO-ANG3, an RNAi drug designed to silence the expression of Angptl3, showed good tolerability over 16 weeks and resulted in the lowering of LDL-C and TRLs in healthy volunteers.…”

“…83 108 The results revealed that Angptl3 RNAi reduced the plasma levels of TG by 50%, HDL-C by 52% and LDL-C by 42.3%. 108 Consistent with this study, a study conducted with RNAi silencing of Angptl3 in mouse liver revealed that Angptl3 deficiency led to lower LDL-C, TG and HDL-C. 71 ARO-ANG3, an RNAi drug designed to silence the expression of Angptl3, showed good tolerability over 16 weeks and resulted in the lowering of LDL-C and TRLs in healthy volunteers. 109 These studies supported the efficacy of Angptl3 RNAi in lowering the plasma concentrations of lipids and shed new light on potential new therapeutic targets for atherosclerosis.…”

“…RNAi therapeutics against Angptl3 mRNA are also being developed. A recent study by Butler et al explored the effects of suppressing Angptl3 expression with RNAi on lipid metabolism in rhesus macaques 108 . The results revealed that Angptl3 RNAi reduced the plasma levels of TG by 50%, HDL‐C by 52% and LDL‐C by 42.3% 108 .…”

Pharmacologic inhibition of ketohexokinase prevents fructose-induced metabolic dysfunction

“…Plasma insulin and triglycerides, hepatic triglycerides, plasma-free fatty acids, plasma apolipoprotein C3, and total plasma cholesterol were elevated in the AD-fed rats compared to the chow-fed rats and decreased by KHK inhibition, parameters of metabolic disease induced by a diet mirroring the average American diet ( Figure 5 B–G). Decreases in circulating adiponectin have been reported in both humans and non-human primates fed fructose [ [48] , [49] , [50] ]. Surprisingly, adiponectin levels did not differ between chow- and AD-fed rats ( Figure 5 H), perhaps due to lower fructose levels in the AD or differences between species.…”