Homozygous loss-of-function ANGPTL3variants are associated with familial combined hypolipidemia, suggesting the dual LPL/EL inhibitor is a promising target for treating atherogenic dyslipidemia. However, nothing is known regarding the dietary regulation of ANGPTL3, including effects of dietary sugar or n-3 fatty acids. We investigated plasma ANGPTL3 concentrations in a rhesus macaque model of high sugar diet-induced dyslipidemia. Animals provided fructose beverages (300 kcal/d) rapidly gain weight (∼10%) and develop insulin resistance and fasting hypertriglyceridemia within 1 month. Fasting plasma ANGPTL3 concentrations increased by 30-40% with fructose consumption after 1 and 3 months (mean±SD in ng/ml; baseline, 60.6±17.4; 1 month, 83.1±25.3; 3 months, 76.9±23.2; both p<0.001 vs. baseline, n=59). Fish oil supplementation (4 g/d) prevents fructose-induced dyslipidemia and completely prevented the increases of ANGPTL3 (-3% vs. +33% over 6 months, p<0.05). Regression modeling to identify lipid/lipoprotein parameters (TG, TC, HDL-C, LDL-C, VLDL-C, APOA1, APOB, APOC3, APOE) explaining variation in ANGPTL3 levels indicated strong correlations with APOC3 at baseline (p=0.002), and APOC3 and APOE after 3 months of fructose (both p<0.05). Regression modeling also examined whether changes (?) of APOC3, APOE, and ANGPTL3 predict ?TG, explaining 41% of variation after 1 month. (R2=0.41, p<0.001). ?APOC3 (B=0.588, p<0.001) and ?ANGPTL3 (B=0.292, p<0.05) were significant predictors in the model. After 3 months, modeling explained 36% of ∆TG (R2=0.36, p<0.001), with all variables contributing significantly (?APOC3, B=0.616, p<0.001; ?ANGPTL3, B=0.245, p<0.05; ?APOE, B= -0.281, p<0.05). Modeling predicted variation of ∆TG before and during fructose consumption (R2=0.294, p=0.033 at baseline; R2=0.438, p<0.001 at 3 months).

In summary, these are the first findings reporting effects of diet composition (sugar and n-3 FAs) on circulating ANGPTL3.


A. Butler: None. J.L. Graham: Research Support; Self; Arrowhead Research, Bristol-Myers Squibb Company, Magnamosis Inc. K.L. Stanhope: None. P.J. Havel: Research Support; Self; Arrowhead Research, Bristol-Myers Squibb Company, Magnamosis Inc.


National Institutes of Health

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