Fructose-induced hypertriglyceridemia in rhesus macaques is attenuated with fish oil or ApoC3 RNA interference

Andrew A. Butler, Candice A. Price, James L. Graham, Kimber Stanhope, Sarah King, Yu Han Hung, Praveen Sethupathy, So Wong, James Hamilton, Ronald M. Krauss, Andrew A. Bremer, Peter J Havel

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Dyslipidemia and insulin resistance are significant adverse outcomes of consuming high-sugar diets. Conversely, dietary fish oil (FO) reduces plasma lipids. Diet-induced dyslipidemia in a rhesus model better approximates the pathophysiology of human metabolic syndrome (MetS) than rodent models. Here, we investigated relationships between metabolic parameters and hypertriglyceridemia in rhesus macaques consuming a high-fructose diet (n = 59) and determined the effects of FO supplementation or RNA interference (RNAi) on plasma ApoC3 and triglyceride (TG) concentrations. Fructose supplementation increased body weight, fasting insulin, leptin, TGs, and large VLDL particles and reduced adiponectin concentrations (all P < 0.001). In multiple regression analyses, increased plasma ApoC3 was the most consistent and significant variable related to diet-induced hypertriglyceridemia. FO supplementation, which attenuated increases of plasma TG and ApoC3 concentrations, reversed fructose-induced shifts of lipoprotein particle size toward IDL and VLDL, a likely mechanism contributing to beneficial metabolic effects, and reduced hepatic expression of genes regulated by the SREBP pathway, particularly acetyl-CoA carboxylase. Furthermore, RNAi-mediated ApoC3 inhibition lowered plasma TG concentrations in animals with diet-induced hypertriglyceridemia. In summary, ApoC3 is an important independent correlate of TG-rich lipoprotein concentrations in rhesus macaques consuming a high-fructose diet. ApoC3 is a promising therapeutic target for hypertriglyceridemia in patients with MetS and diabetes.

Original languageEnglish (US)
Pages (from-to)805-818
Number of pages14
JournalJournal of lipid research
Volume60
Issue number4
DOIs
StatePublished - Apr 1 2019

Fingerprint

Fish Oils
Hypertriglyceridemia
Nutrition
RNA Interference
Fructose
Macaca mulatta
RNA
Diet
Plasmas
Triglycerides
Dyslipidemias
Lipoproteins
Insulin
Unsaturated Dietary Fats
Acetyl-CoA Carboxylase
Adiponectin
Medical problems
Leptin
Particle Size
Sugars

Keywords

  • acetyl-coenzyme A carboxylase
  • apolipoprotein C3
  • apolipoproteins
  • diet effects/lipid metabolism
  • lipogenic enzymes
  • nonhuman primate models
  • nutrition/carbohydrate
  • ribonucleic acid interference

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

Cite this

Fructose-induced hypertriglyceridemia in rhesus macaques is attenuated with fish oil or ApoC3 RNA interference. / Butler, Andrew A.; Price, Candice A.; Graham, James L.; Stanhope, Kimber; King, Sarah; Hung, Yu Han; Sethupathy, Praveen; Wong, So; Hamilton, James; Krauss, Ronald M.; Bremer, Andrew A.; Havel, Peter J.

In: Journal of lipid research, Vol. 60, No. 4, 01.04.2019, p. 805-818.

Research output: Contribution to journalArticle

Butler, AA, Price, CA, Graham, JL, Stanhope, K, King, S, Hung, YH, Sethupathy, P, Wong, S, Hamilton, J, Krauss, RM, Bremer, AA & Havel, PJ 2019, 'Fructose-induced hypertriglyceridemia in rhesus macaques is attenuated with fish oil or ApoC3 RNA interference', Journal of lipid research, vol. 60, no. 4, pp. 805-818. https://doi.org/10.1194/jlr.M089508
Butler, Andrew A. ; Price, Candice A. ; Graham, James L. ; Stanhope, Kimber ; King, Sarah ; Hung, Yu Han ; Sethupathy, Praveen ; Wong, So ; Hamilton, James ; Krauss, Ronald M. ; Bremer, Andrew A. ; Havel, Peter J. / Fructose-induced hypertriglyceridemia in rhesus macaques is attenuated with fish oil or ApoC3 RNA interference. In: Journal of lipid research. 2019 ; Vol. 60, No. 4. pp. 805-818.
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AU - Stanhope, Kimber

AU - King, Sarah

AU - Hung, Yu Han

AU - Sethupathy, Praveen

AU - Wong, So

AU - Hamilton, James

AU - Krauss, Ronald M.

AU - Bremer, Andrew A.

AU - Havel, Peter J

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N2 - Dyslipidemia and insulin resistance are significant adverse outcomes of consuming high-sugar diets. Conversely, dietary fish oil (FO) reduces plasma lipids. Diet-induced dyslipidemia in a rhesus model better approximates the pathophysiology of human metabolic syndrome (MetS) than rodent models. Here, we investigated relationships between metabolic parameters and hypertriglyceridemia in rhesus macaques consuming a high-fructose diet (n = 59) and determined the effects of FO supplementation or RNA interference (RNAi) on plasma ApoC3 and triglyceride (TG) concentrations. Fructose supplementation increased body weight, fasting insulin, leptin, TGs, and large VLDL particles and reduced adiponectin concentrations (all P < 0.001). In multiple regression analyses, increased plasma ApoC3 was the most consistent and significant variable related to diet-induced hypertriglyceridemia. FO supplementation, which attenuated increases of plasma TG and ApoC3 concentrations, reversed fructose-induced shifts of lipoprotein particle size toward IDL and VLDL, a likely mechanism contributing to beneficial metabolic effects, and reduced hepatic expression of genes regulated by the SREBP pathway, particularly acetyl-CoA carboxylase. Furthermore, RNAi-mediated ApoC3 inhibition lowered plasma TG concentrations in animals with diet-induced hypertriglyceridemia. In summary, ApoC3 is an important independent correlate of TG-rich lipoprotein concentrations in rhesus macaques consuming a high-fructose diet. ApoC3 is a promising therapeutic target for hypertriglyceridemia in patients with MetS and diabetes.

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