TY - JOUR
T1 - ANGPTL3 (Angiopoietin-Like 3) Preferentially Resides on High-Density Lipoprotein in the Human Circulation, Affecting Its Activity
AU - Kraaijenhof, Jordan M.
AU - Tromp, Tycho R.
AU - Nurmohamed, Nick S.
AU - Reeskamp, Laurens F.
AU - Langenkamp, Marije
AU - Levels, Johannes H. M.
AU - Boekholdt, S. Matthijs
AU - Wareham, Nicholas J.
AU - Hoekstra, Menno
AU - Stroes, Erik S. G.
AU - Hovingh, G. Kees
AU - Grefhorst, Aldo
N1 - Funding Information: This work was supported by the Netherlands Organization for Scientific Research (VIDI grant 016.156.445). Funding Information: Nick S. Nurmohamed and Laurens F. Reeskamp are cofounders of LipidTools BV. Erik S. G. Stroes has received fees paid to his institution from Amgen, Akcea, Athera, Sanofi-Regeneron, Esperion, Novo Nordisk, Lilly, and Novartis. G. Kees Hovingh has received institutional research support from Aegerion, Amgen, AstraZeneca, Eli Lilly, Genzyme, Ionis, Kowa, Pfizer, Regeneron, Roche, Sanofi, and The Medicines Company; speaker’s bureau and consulting fees from Amgen, Aegerion, Sanofi, and Regeneron (fees paid to the academic institution). G. Kees Hoving has part-time employment at Novo Nordisk. The remaining authors have no disclosures to report. Publisher Copyright: © 2023 The Authors.
PY - 2023/11/7
Y1 - 2023/11/7
N2 - BACKGROUND: ANGPTL3 (angiopoietin-like protein 3) is an acknowledged crucial regulator of lipid metabolism by virtue of its in-hibitory effect on lipoprotein lipase and endothelial lipase. It is currently unknown whether and to which lipoproteins ANGPTL3 is bound and whether the ability of ANGPTL3 to inhibit lipase activity is affected by binding to lipoproteins. METHODS AND RESULTS: Incubation of ultracentrifugation-isolated low-density lipoprotein (LDL) and high-density lipoprotein (HDL) fractions from healthy volunteers with recombinant ANGPTL3 revealed that ANGPTL3 associates with both HDL and LDL particles ex vivo. Plasma from healthy volunteers and a patient deficient in HDL was fractionated by fast protein liq-uid chromatography, and ANGPTL3 distribution among lipoprotein fractions was measured. In healthy volunteers, ≈75% of lipoprotein-associated ANGPTL3 resides in HDL fractions, whereas ANGPTL3 was largely bound to LDL in the patient deficient in HDL. ANGPTL3 activity was studied by measuring lipolysis and uptake of3 H-trioleate by brown adipocyte T37i cells. Unbound ANGPTL3 did not suppress lipase activity, but when given with HDL or LDL, ANGPTL3 suppressed lipase activity by 21.4±16.4% (P=0.03) and 25.4±8.2% (P=0.006), respectively. Finally, in a subset of the EPIC (European Prospective Investigation into Cancer) Norfolk study, plasma HDL cholesterol and amount of large HDL particles were both positively associated with plasma ANGPTL3 concentrations. Moreover, plasma ANGPTL3 concentrations showed a positive association with incident coronary artery disease (odds ratio, 1.25 [95% CI, 1.01–1.55], P=0.04). CONCLUSIONS: Although ANGPTL3 preferentially resides on HDL, its activity was highest once bound to LDL particles.
AB - BACKGROUND: ANGPTL3 (angiopoietin-like protein 3) is an acknowledged crucial regulator of lipid metabolism by virtue of its in-hibitory effect on lipoprotein lipase and endothelial lipase. It is currently unknown whether and to which lipoproteins ANGPTL3 is bound and whether the ability of ANGPTL3 to inhibit lipase activity is affected by binding to lipoproteins. METHODS AND RESULTS: Incubation of ultracentrifugation-isolated low-density lipoprotein (LDL) and high-density lipoprotein (HDL) fractions from healthy volunteers with recombinant ANGPTL3 revealed that ANGPTL3 associates with both HDL and LDL particles ex vivo. Plasma from healthy volunteers and a patient deficient in HDL was fractionated by fast protein liq-uid chromatography, and ANGPTL3 distribution among lipoprotein fractions was measured. In healthy volunteers, ≈75% of lipoprotein-associated ANGPTL3 resides in HDL fractions, whereas ANGPTL3 was largely bound to LDL in the patient deficient in HDL. ANGPTL3 activity was studied by measuring lipolysis and uptake of3 H-trioleate by brown adipocyte T37i cells. Unbound ANGPTL3 did not suppress lipase activity, but when given with HDL or LDL, ANGPTL3 suppressed lipase activity by 21.4±16.4% (P=0.03) and 25.4±8.2% (P=0.006), respectively. Finally, in a subset of the EPIC (European Prospective Investigation into Cancer) Norfolk study, plasma HDL cholesterol and amount of large HDL particles were both positively associated with plasma ANGPTL3 concentrations. Moreover, plasma ANGPTL3 concentrations showed a positive association with incident coronary artery disease (odds ratio, 1.25 [95% CI, 1.01–1.55], P=0.04). CONCLUSIONS: Although ANGPTL3 preferentially resides on HDL, its activity was highest once bound to LDL particles.
KW - adipocytes
KW - atherosclerosis
KW - cholesterol
KW - drug therapy/hypolipidemic drugs
KW - lipase/lipoprotein
KW - triglycerides
UR - http://www.scopus.com/inward/record.url?scp=85176496520&partnerID=8YFLogxK
U2 - https://doi.org/10.1161/JAHA.123.030476
DO - https://doi.org/10.1161/JAHA.123.030476
M3 - Article
C2 - 37889183
SN - 2047-9980
VL - 12
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
IS - 21
M1 - e030476
ER -