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

Andrew A. Butler, James L. Graham, Kimber L. Stanhope, So Wong, Sarah King, Andrew Bremer, Ronald M. Krauss, James Hamilton, Peter J. Havel

Research output: Contribution to journalArticle

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 insulinsensitizing 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.

Original languageEnglish (US)
Pages (from-to)376-386
Number of pages11
JournalJournal of lipid research
Volume61
Issue number3
DOIs
StatePublished - Jan 1 2020

Keywords

  • Apolipoproteins
  • C-reactive protein
  • Inflammation
  • Insulin resistance
  • Lipoproteins
  • Metabolic disorders
  • Nonhuman primate
  • RNA interference
  • Triglycerides

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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  • Cite this

    Butler, A. A., Graham, J. L., Stanhope, K. L., Wong, S., King, S., Bremer, A., Krauss, R. M., Hamilton, J., & Havel, P. J. (2020). Role of angiopoietin-like protein 3 in sugar-induced dyslipidemia in rhesus macaques: Suppression by fish oil or RNAi. Journal of lipid research, 61(3), 376-386. https://doi.org/10.1194/jlr.RA119000423