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Role of angiopoietin-like protein 3 in sugar-induced dyslipidemia in rhesus
macaques: suppression by fish oil or RNAi.
Authors Butler AA, Graham JL, Stanhope KL, Wong S, King S, Bremer AA, Krauss RM,
Hamilton J, Havel PJ
Submitted By Submitted Externally on 3/26/2020
Status Published
Journal Journal of lipid research
Year 2020
Date Published 3/1/2020
Volume : Pages 61 : 376 - 386
PubMed Reference 31919051
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.


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